CN1756747A - Anti-inflammatory medicaments - Google Patents
Anti-inflammatory medicaments Download PDFInfo
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- CN1756747A CN1756747A CN 200380110050 CN200380110050A CN1756747A CN 1756747 A CN1756747 A CN 1756747A CN 200380110050 CN200380110050 CN 200380110050 CN 200380110050 A CN200380110050 A CN 200380110050A CN 1756747 A CN1756747 A CN 1756747A
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Abstract
Novel compounds and methods of using those compounds for the treatment of oncological conditions are provided. In a preferred embodiment, modulation of the activation states of abl or bcr-abl alpha-kinase proteins comprises the step of contacting the kinase proteins with the novel compounds.
Description
Background of invention
Related application
The application requires the provisional application S/N 60/437 that is entitled as " method (Process ForModulating Protein Function) of regulating protein function " of submission on December 31st, 2002,487, that submitted on December 31st, 2002 is entitled as " the provisional application S/N 60/437 of cancer therapy drug (Anti-Cancer Medicaments); 403; the provisional application S/N 60/437 that is entitled as " anti-inflammatory medicaments (Anti-Inflammatory Medicaments) " that on December 31st, 2002 submitted to; 415; the provisional application S/N 60/437 that is entitled as " anti-inflammatory medicaments (Anti-InflammatoryMedicaments) " that on December 31st, 2002 submitted to; 304, interests with the provisional application S/N 60/463,804 that is entitled as " medicines (Medicaments For the Treatment ofNeurodegenerative DiSOrders or Diabetes) of treatment neurodegenerative disease or diabetes " that submitted on April 18th, 2003.These applications are included this paper respectively in as a reference.
Invention field
The present invention relates to the method for new compound and these compounds for treating anti-inflammatory diseases of use.
The description of prior art
Recently, fundamental research provides a large amount of human inheritance's coded messages for life science mechanism and by protein that these genetic codings produced.Complete sequence (Lander, E.S. etc., the Initial sequencing and analysis of the human genome of human genome have been reported in calendar year 2001; Nature (2001) 409:860; Venter, J.C. etc., The sequence of the human genome, Science (2001)
291:1304).The research institution in the whole world classifies 50,000 polyprotein matter of these genetic sequence codings now, the more important thing is and attempts the protein that those become the reason of the main human diseases that lacks treatment.Although human genome and proteinic information value thereof are provided, especially in the field of protein function conformation control, pharmaceutical industry set about in order to the method that begins to develop the small molecules therapeutical agent and strategy with the natural protein reactive site aspect the small molecules therapeutical agent, not obtain remarkable break-throughs.These natural reactive sites are used for carrying out essential cell function by protein usually, by in conjunction with and process natural substrate or from the native ligand transduction signal.Because these natural pockets are extensive use of by many other protein in the protein families, thus selectivity lacked usually with their interactional medicines, therefore not enough so that the treatment window reaches maximum effect.These small molecules also have side effect and toxicity, no matter find before clinical, during the clinical trial or later on market.Side effect and toxicity are still the major cause of high damage rate in the drug discovery process.With regard to proteinic kinase protein family, the interaction of these natural reactive sites is summarized recently: referring to J.Dumas, Emerging Pharmacophores:1997-2000, Expert Opinion on TherapeuticPatents (2001) 11:405-429; J.Dumas compiles, and the new problem in the protein kinase restraining effect is published in Current Topics in Medicinall Chemistry (2002)
2: the 9th phase.
Known protein matter has flexible, and this flexibility has been in the news and has been used to find the flexible reactive site bonded small molecules possible with protein.Summary for this proposition can be referring to Teague, Nature Reviews/DrugDiscovery, 2 volumes, 527-541 page or leaf (2003).Also can be referring to Wu etc., Structure, 11 volumes, 399-410 page or leaf (2003).Yet these reports are paid close attention to is only at the small molecules of protein natural radioactivity position conjugated protein.Peng etc., Bio.Organic andMedieinal ChemistryLtrs., 13 volumes, 3693-3699 page or leaf (2003) and Schindler etc., Science, 289 volumes, 1938 pages (2000) have described the kinase whose inhibitor of abl.These inhibitor are differentiated in WO publication No.2002/034727.This class inhibitor is in conjunction with the ATP reactive site, the mode combination of also moving with inducible kinase catalysis ring simultaneously.Pargellis etc., Nature Structural Biology, 9 volumes, p.268 the inhibitor p38 Dihydrostreptomycin-6-phosphate 3'alpha-kinase of (2002) report also is disclosed in WO publication No.00/43384 and Regan etc., J Medicinal Chemistry, 45 volumes are in the 2994-3008 page or leaf (2002).This class inhibitor is also being followed mobile relevant ATP reactive site and kinase interactions with the kinase activation ring.
Recently, disclose kinases utilization activation ring and kinase domain adjusting pocket (kinase domaiNRegulatorypocket) and controlled their catalytic activity state.Summarize recently, can be referring to M.Huse and J.Kuriyan, Cell (2002) 109:275.
Summary of the invention
The present invention is broadly directed to the new compound of treatment anti-inflammatory disease and the method for the treatment of this disease.In more detail, The compounds of this invention has following structural formula:
In the formula:
R
1Be selected from aryl (better C
6-C
18, better C
6-C
12And heteroaryl; X and Y are selected from independently of one another :-O-,-S-,-NR
6-,-NR
6R6SO
2-,-N
R6CO-, alkynyl (better C
1-C
18, better C
1-C
12), thiazolinyl (better C
1-C
18, better C
1-C
12), alkylidene group (better C
1-C
18, better C
1-C
12) ,-O (CH
2)
h-and-NR
6(CH
2)
h-, wherein h is selected from independently of one another: 1,2,3 or 4, wherein, to alkylidene group (better C-C
18, better C
1-C
12) ,-O (CH
2)
h-and-NR
6(CH
2)
h-in each, wherein one of methylene radical of Cun Zaiing can be chosen two keys wantonly and be connected to side chain oxygen base, except-O (CH
2)
h-, introduce side chain oxygen base and do not form ester moiety;
A is selected from: aromatics (better C
6-C
18, better C
6-C
12), monocyclic heterocycles, and bicyclic heterocycles;
D is phenyl or five-unit or six-first heterocycle: be selected from pyrazolyl, pyrryl, imidazolyl ， oxazolyl, thiazolyl, furyl, pyridyl and pyrimidyl;
E is selected from: phenyl, pyridyl and pyrimidyl;
L is selected from :-C (O)-and-S (O)
2-;
J is 0 or 1;
M is 0 or 1;
N is 0 or 1;
P is 0 or 1;
Q is 0 or 1;
T is 0 or 1;
Q is selected from following:
R
4Group is selected from independently of one another :-H, alkyl (better C
1-C
18, better C
1-C
12), aminoalkyl group (better C
1-C
18, better C
1-C
12), alkoxyl group acyl group (better C
1-C
18, better C
1-C
12), aryl (better C
6-C
18, better C
6-C
12), aralkyl (better C
6-C
18, better C
6-C
12And better C
1-C
18, better C
1-C
12), heterocyclic radical and Heterocyclylalkyl are except when R
4Substituting group is placed with a heteroatoms on the α carbon that is directly connected to ring nitrogen on the Q;
As two R
4When group is connected with same atom, two R
4Optional 4-7 unit's alicyclic ring or the heterocycle of forming of group;
R
5Be selected from independently of one another :-H, alkyl (better C
1-C
18, better C
1-C
12), aryl (better C
6-C
18, better C
6-C, 2), heterocyclic radical, alkylamino (better C-C
18Better C ,-C
12), arylamino (better C
6-C
18, better C
6-C
12), cycloalkyl amino (better C
1-C
18, better C
1-C
12), heterocyclic radical amino, hydroxyl, alkoxyl group (better C
1-C
18, better C
1-C, 2), aryloxy (better C
6-C
18, better C
6-C
12), alkylthio (better better C
1-C
12), arylthio (better C
6-C
18, better C
6-C, 2), cyano group, halogen, perfluoroalkyl (better C
1-C
18, better C
1-C
12), alkyl-carbonyl (better C
1-C
18, better C
1-C
12) and nitro;
R
6Be selected from independently of one another :-H, alkyl (better C
1-C
18, better C
1-C
12), allyl group and β-trimethyl silyl ethyl;
R
8Be selected from independently of one another: alkyl (better C
1-C
18, better C
1-C
12), aralkyl (better C
6-C
18, better C
6-C
12And better C
1-C
18, better C
1-C
12), heterocyclic radical and Heterocyclylalkyl (better C
1-C
18, better C-C
12);
R
9Group is selected from independently of one another :-H ,-F and alkyl (better C
1-C
18, better C
1-C
12), wherein, as two R
9When group was the alkyl of geminal, the alkyl of described geminal can cyclisation form a 3-6 unit ring;
Z is selected from independently of one another :-O-and-N (R
4)-;
Each ring is chosen wantonly and is comprised one or more R in the formula (I)
7, R wherein
7Be non-interfering substituent, be independently selected from :-H, alkyl (better C
1-C
18, better C
1-C
12), aryl (better C
6-C
1,, better C
6-C
12), heterocyclic radical, alkylamino (better C
1-C
18, better C
1-C
12), arylamino (better C
6-C
18, better C
6-C
12), cycloalkyl amino (better C
1-C
18, better C
1-C
12), heterocyclic radical amino, hydroxyl, alkoxyl group (better C
1-C
18, better C
1-C
12), aryloxy (better C
6-C
18, better C
6-C
12), alkylthio (better C
1-C
18, better C
1-C
12), arylthio, cyano group, halogen, nitrilo, nitro, alkyl sulfinyl (better C
1-C
18, better C
1-C
12), alkyl sulphonyl (better C
1-C
18, better C
1-C
12), amino-sulfonyl and perfluoroalkyl (better C
1-C
18, better C
1-C
12).
In the better embodiment, compound has the structure of formula (I), except: when Q was Q-3 or Q-4, then formula (I) compound was not following compound:
When Q was Q-7, q was 0, R
5With D be phenyl, then A is not a phenyl ， oxazolyl, pyridyl, pyrimidyl, pyrazolyl or imidazolyl;
When Q is Q-7, R
5Be-OH, Y is-O-,-S-or-CO-, m is 0, n is 0, p be 0 and A be phenyl, pyridyl or thiazolyl, then D is not a thienyl, thiazolyl or phenyl;
When Q is Q-7, R
5Be-OH, m is 0, and n is 0, and p is 0, t be 0 and A be phenyl, pyridyl or thiazolyl, then D is not a thienyl, thiazolyl or phenyl;
When Q was Q-7, then formula (I) compound was not a following compounds:
R
80Be H, Me R
81It is the phenyl that replaces
R
82It is the phenyl that replaces
When Q was Q-8, then Y was not-CH
2O-;
When Q was Q-8, formula (I) compound was not a following compounds:
R
10=alkyl, aryl, alkoxy aryl alkyl or aralkyl
When Q was Q-9, then formula (I) compound was not a following compounds:
R
11=H, alkyl, alkoxyl group, R
12, R
13=H, alkyl R
14=H, alkyl, allyl group, propargyl
Nitro, halogen R
15=H, alkyl
, or
R
16=H, methyl R
17, R
118=alkyl
R
10=H
1Alkyl
When Q is Q-10, t be 0 and E be phenyl, then E goes up any R
7It or not the o-alkoxyl group;
When Q was Q-10, then formula (I) compound was not following compound:
When Q was Q-11, t was 0 and the E phenyl, and then E goes up any R
7It or not the o-alkoxyl group;
When Q was Q-11, then formula (I) compound was not following compound:
When Q was Q-15, then formula (I) compound was not following compound:
R
20The phenyl of=replacement, R
21=H, alkyl
When Q is Q-16, Y is-during NH-,
Then the following compound of formula (I) is not an xenyl;
When Q is Q-16, Y is-during S-, then the following compound of formula (I) is not phenyl sulfonyl amino phenyl or phenylcarbonyl group aminophenyl;
When Q is Q-16, Y is-SO
2During NH-, then formula (I) compound is not a following compounds:
R
23＝OH，SH，NH
2
R
24=H or-individual or a plurality of methoxyl groups, hydroxyl, fluorine, chlorine, nitro,
Dimethylamino, or furyl
R
25The phenyl of=replacement, furyl
R
26=OH or Cl
X
5＝O，NH
When Q is Q-16, Y is-during CONH-, then the following compound of formula (I) is not the imidazo phenyl;
When Q is Q-16, Y is-during CONH-, then formula (I) compound is not following compound:
R
27The phenyl of=replacement, the pyridine carbonyl
R
28=CN, methoxycarbonyl
N=0 or 1
When Q is Q-16, t is 0 o'clock,
Then the following compound of formula (I) is not the phenylcarbonyl group phenyl, Mi Dingbing phenyl, phenyl pyrimidine base, pyrimidyl or N-pyrryl;
When Q was Q-17, then formula (I) compound was not following compound:
Or
R
29=alkyl R
31The phenyl R of=replacement
30=H, the tertiary butyl, benzoyl
When Q was Q-21, then formula (I) compound was not following compound:
When Q was Q-22, then formula (I) compound was selected from following:
When Q is Q-22, q is 0 o'clock, and then formula (I) compound is selected from following:
But do not comprise following compounds:
Between or to R
34=Me, C
1Between or to R
37=N (Me)
2, morpholino, OMe, OH, H
R
35=N (Me)
2, morpholino R
38=H, CN, OMe, OH, benzyloxy, phenyl,
R
36=H, the F nitro
R
39＝H，OH
R
40＝H，F
R
41＝H，C
1
Between or to or right
Between or right
When Q was Q-23, then formula (I) compound was not a following compounds:
When Q is Q-24, Q-25, when Q-26 or Q-31, then formula (I) compound is selected from following:
Wherein, W is selected from independently of one another :-CH-and-N-;
G
1Be independently selected from :-O-,-S-and-N (R
4)-; With
* mark the following Q-24 of being connected to, Q-25, the site of Q-26 or Q-31:
Q-24 Q-25 Q-26 or Q-31
Wherein, Z is selected from independently of one another :-O-and-N (R
4)-;
When Q was Q-31, then formula (I) compound was not following compound:
Or
When Q is Q-28 or Q-29, t is 0 o'clock, and then formula (I) compound is not following compound:
R
46=H, hydroxyalkyl, alkoxyl group alkoxyl group, hydroxyl
When Q is Q-28 or Q-29, when Y was ehter bond, then formula (I) compound was not following compound:
Or
When Q is Q-28 or Q-29, Y is-during CONH-, then formula (I) compound is not following compound:
When Q was Q-32, then following compound was not an xenyl, benzoxazolyl phenyl, pyridyl phenyl or bipyridyl;
When Q is Q-32, Y is-CONH-, and q is 0, and m is 0, and the following formula of formula (I) is-and during CONH-, then A is not a phenyl;
When Q was Q-32, q was 0, and m is 0, following formula is-and during CONH-,
Then formula (I) compound is not following compound:
R
42=alkyl, the phenyl of replacement, thienyl, phenylacetyl, naphthyl R
54=benzoyl, the Phenylalkylamino carbonyl replaces
R
48=H, alkyl, Br, the phenyl of replacement, benzoyl, the phenyl amino carbonyl of phenyl sulphur, H, Br
Acyl group R
55=Cl, Br, SPh, benzoyl, phenyl sulfonyl
R
49=H, alkyl, phenyl R
51=H, phenyl sulfonyl, phenyl, benzyl
R
50The phenyl R of=replacement
6=Et, i-Pr
R
53The phenyl of=replacement, the benzyl of replacement
X
1=O, N-Ph, N-alkyl, N-formamyl
Z
1＝N(R
5O)，O
When Q is Q-32, D is a thiazolyl, and q is 0, and t is 0, and p is 0, n be 0 and m be 0 o'clock, then A is not phenyl or 2-pyridone;
When Q is Q-32, D be uh azoles base Huo isoxazolyl, q is 0, t is 0, p is 0, n be 0 and m be 0 o'clock, then A is not a phenyl:
When Q is Q-32, D is that pyrimidyl q is 0, and t is 0, and p is 0, n be 0 and m be 0 o'clock, then A is not a phenyl;
When Q is Q-32, when Y was ehter bond, then the following formula of formula (I) was not xenyl or Ben Ji oxazolyl;
When Q is Q-32, Y is-during CH=CH-, then the following formula of formula (I) is not the phenyl amino phenyl:
When Q was Q-32, then formula (I) compound was not following compound:
R
58The alkyl amino-carbonyl of=replacement, phenyl amino carbonyl d=0.2
R
59=H, Cl R
60=H, alkyl R
61The phenyl of=replacement, thienyl, Br
R
62=H, alkyl, phenyl
R
63The phenyl of=replacement
When Q is Q-35, as follows:
Q-35 (to) Q-35 ()
Wherein G is selected from :-O-,-S-,-NR
4-and-CH
2-, k be 0 or 1 and u be 1,2,3 or 4, following formula then
Be selected from following:
Except formula (I) compound is not following:
R
71=H, Me R
72=thiazolyl ， isoxazolyl, imidazoles 28.1 R
73=OCH
2CO
2Between H, right
W
4=N, CH base, furyl R
74The=oxazolyl, imidazolyl R
75=H, Et
28.2 R
73＝CO
2Me R
76＝H，NH
2，NO
2
R
74=chloro-phenyl-n=0-1
Better, R as discussed above
1Be selected from: the 6-5 condensed heteroaryl, 6-5 annelated heterocycles base, 5-6 condensed heteroaryl and 5-6 annelated heterocycles base, best, R
1Be selected from following:
R
2Be selected from independently of one another :-H, alkyl (better C
1-C
18, better C
1-C
12), amino, alkylamino (better C
1-C
18, better C
1-C
12), arylamino (better C
6-C
18, better C
6-C
12), cycloalkyl amino (better C
1-C
18, better C
1-C
12), heterocyclic radical amino, halogen, alkoxyl group (better C
1-C
18, better C
1-C
12) and hydroxyl;
R
3Be selected from independently of one another :-H, alkyl (better C
1-C
18, better C
1-C
12), alkylamino (better C
1-C
18, better C
1-C
12), arylamino (better C
6-C
18, better C
6-C
12), cycloalkyl amino (better C
1-C
18, better C-C
12), heterocyclic radical amino, alkoxyl group (better C
1-C
18, better C
1-C
12), hydroxyl, cyano group, halogen, perfluor allyl group (better C
1-C
18, better C
1-C
12), alkyl sulfinyl (better C
1-C
18, better C
1-C
12), alkyl sulphonyl (better C
1-C
18, better C
1-C
12), R
4NHSO
2-and-NHSO
2R
4
V is selected from: O and H
2
At last, in another embodiment, A as described above is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrryl, thiazolyl ， oxazolyl, imidazolyl, indyl, indazolyl, benzimidazolyl-, benzotriazole base, isoquinolyl, quinolyl, benzothiazolyl, benzofuryl, benzothienyl, the pyrazolyl pyrimidyl, the imidazopyrimidine base, purine radicals and
Wherein, W
1Be selected from independently of one another :-CH-and-N-.
As for method of the present invention, determine kinase whose active state by the interaction of on-off control part and complementary on-off control pocket.Kinase whose a kind of conformation is from the interaction of on-off control part with concrete on-off control pocket, and another kind of conformation is from the interaction of part with different on-off control pockets simultaneously.Usually, part and a pocket, the interaction of for example " opening " pocket obtains being assumed to be the kinases of activity conformation, and wherein, described kinases is bioactive.Similarly, when part and another kind of on-off control pocket, when for example " pass " pocket interacts, be assumed to the conformation (wherein, kinases is not bioactive) of inactivation.Described on-off control pocket is selected from on-off control pocket single, compound and combination.Interaction between described on-off control part and the on-off control pocket is dynamic, and therefore, described part does not always interact with the on-off control pocket.In some cases, described part is not at on-off control pocket (as occurring when activity conformation becomes the inactivation conformation when protein).In other cases, for example when part with around proteinic environmental interaction, when with definite and which on-off control pocket interacting, described part is not in the on-off control pocket.The interaction of described part and concrete on-off control pocket partly is controlled by the state of charge of the amino-acid residue of on-off control part.When described part was the electric neutrality state, it and an on-off control pocket interacted, and when it was electriferous state, it and other on-off control pocket interacted.For example, described on-off control part has many OH groups, and is in the neutral charge state.This neutral charge state more may interact part by the hydrogen bond between OH group and the selected pocket residue and an on-off control pocket, produces thus from the interacting proteins conformation.But, if the OH group of described on-off control part becomes electrically charged by phosphorylation or some alternate manners, the interactional tendency of described part and other on-off control pocket increases, complementary covalent linkage and this other on-off control pocket interaction between the residue of the electronegative or positive electricity that described part will be by pocket and part.When described part is the neutral charge state, and when interacting, cause described protein to be the phase anticonformation of being supposed with other on-off control pocket.
Certainly, proteinic conformation has been determined proteinic active state, therefore, with protein diseases associated, process and illness in play an important role.For example, if metabolic process needs bioactive protein, still, described protein switch control part is stayed in the on-off control pocket (that is, " pass " pocket), forms the protein of bioinactivation, and described metabolic process can not occur with usual dispatch.Similarly, because of bioactive protein rapid deterioration, described protein switch control part people stays in the on-off control pocket (that is, " opening " pocket), forms bioactive protein conformation as if disease, and described illness will worsen.Therefore, as proving, take molecule by selectivity and come selectivity by-pass cock control pocket and on-off control part in treatment and control and protein diseases associated, process and illness, to play an important role by the present invention.
One aspect of the present invention provides a kind of adjusting kinases, better is the p38 Dihydrostreptomycin-6-phosphate 3'alpha-kinase active state of (comprising total wild-type sequence and disease polymorph).Described active state is selected from adjusted (upregulated) usually and regulates (downregulated) state down.Described method generally includes the step that kinases is contacted with the molecule with general formula (I).When this contact occurs, described molecule is attached on the concrete on-off control pocket, described on-off control part is more prone to interact with other on-off control pocket (that is, the pocket that does not occupy), and the opening control pocket interaction of not too tending to and having occupied.As a result, described protein is more prone to be assumed to be the conformation (therefore, by adjusted or adjusting down) of activation or inactivation, and this depends on which on-off control pocket is occupied by molecule.Therefore, kinases is contacted with molecule and regulated proteinic active state.Described molecule can be used as the antagonist or the agonist of arbitrary on-off control pocket.Contact the zone that better comes across kinases on-off control pocket between molecule and the kinases, be more preferably between kinase whose leaf in the oxygen anion pocket.In some cases, the contact between molecule and the pocket also can change the conformation of other adjacent regions and pocket, as the ATP reactive site.This variation also can influence the adjusting and the adjusting of protein active state.Be preferably, described kinase whose on-off control pocket area comprises amino acid residue sequence, its exercisable being attached on the molecule shown in the general formula I.This combination is present in molecule and has between the specific region of on-off control pocket of favored area, and described favored area comprises α-C spiral, α-D spiral, catalysis ring, activation ring and C-terminal residue or C-leaf residue (all residues are positioned at the downstream (to the C-end) of activation ring) and their combination.When calmodulin binding domain CaM was α-C spiral, a preferred combination sequence in this spiral was sequence IIXXKRXXREXXLLXXM (SEQ ID NO.2).When described calmodulin binding domain CaM was the catalysis ring, a preferred combination sequence in this ring was DIIHRD (SEQ ID NO.3).When described calmodulin binding domain CaM is when ring activation, a preferred combination sequence in this ring be selected from DFGLSARHTDD (SEQ IDNO.4), EMTGYVATRWYR (SEQ ID NO.5) with and combination.When described calmodulin binding domain CaM was in C-leaf residue, a preferred binding sequence was WMHY (SEQ ID No.6).When needing the protein conformation of bioinactivation, will select and the interactional molecule of on-off control pocket, form biological activity protein conformation (when the time) usually with the on-off control ligand interaction.Similarly, when needs biological activity protein conformation, select and the interactional molecule of on-off control pocket, form the protein conformation (when the time) of bioinactivation usually with the on-off control ligand interaction.Therefore, proteinic tendency is assumed to be required conformation and will regulates by taking described molecule.In a preferred form, take described molecule, to treat separately, described treatment is selected from: people's inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, urarthritis, Sepsis, septic shock, endotoxin shock, Gram-negative farming toxication, toxic shock syndrome, adult respiratory distress syndrome, apoplexy, reperfusion injury, neural wound, neural ischemic, psoriatic, restenosis, chronic pulmonary inflammatory disease, the bone resorption disease, graft-vs-host reaction, ChronShi disease, ulcerative colitis, inflammatory bowel, pyrosis, and their combination.In this form, need to select and the interactional molecule of on-off control pocket, this forms the biological activity protein conformation usually, makes protein tend to suppose the form of described bioinactivation, alleviates illness thus.Estimate that the form that molecule of the present invention can any routine takes, comprise oral, parenteral, suction and subcutaneous.Preferably take with oral form.Preferred molecule comprises compound shown in the above-mentioned preferred general formula I.
The present invention provides a kind of method for the treatment of inflammation on the other hand, and described method comprises to individuality takes the have general formula step of molecule of (I).This illness is understood the protein that excess produces biologically active form usually, comprises kinases.
The described step of taking generally includes the kinases (preferred p38 alpha kinase) that makes the contact of described molecule relate to inflammatory process.When contacting between molecule and the kinases, described contact better comes across between kinase whose leaf in the oxygen anion pocket, and it comprises and operationally is attached to the amino acid residue sequence on the molecule shown in the general formula I.The preferred combination zone of oxygen anion pocket comprises α-C spiral zone, α-D spiral zone, catalysis ring, activation ring, C-terminal residue and their combination between leaf.When described calmodulin binding domain CaM is α-C spiral, a preferred combination sequence in this spiral is sequence IIXXKRXXREXXLLXXM (SEQ ID NO.2).When described calmodulin binding domain CaM was the catalysis ring, a preferred combination sequence in this ring was DIIGRD (SEQ ID NO.3).When described calmodulin binding domain CaM was the activation ring, a preferred combination sequence in this ring was the sequence that is selected from DFGARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO.5) and their combination.
This method allows to treat illness by kinases is contacted with molecule (relevant with the on-off control pocket) by regulating kinase whose active state, in the above-mentioned contact procedure, when with the on-off control ligand interaction, forms kinase whose biologically active form usually.Because part is not easy to interact with on-off control pocket (relevant with molecule or occupied by molecule), described part and on-off control pocket interact, the protein of formation bioinactivation form.Be preferably, described illness is selected from people's inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, urarthritis, Sepsis, septic shock, endotoxin shock, Gram-negative farming toxication, toxic shock syndrome, adult respiratory distress syndrome, apoplexy, reperfusion injury, neural wound, neural ischemic, psoriatic, restenosis, chronic pulmonary inflammatory disease, the bone resorption disease, graft-vs-host reaction, ChronShi disease, ulcerative colitis, inflammatory bowel, pyrosis, and their combination.As for other method of the present invention, described molecule can be taken by arbitrary conventionally form, has any conventional vehicle or composition.But, preferably take the molecule of oral dosage form.Preferred molecule is selected from preferred compound shown in the above-mentioned general formula (I) once more.
The accompanying drawing summary
Fig. 1 is the synoptic diagram of the mammalian proteins matter of natural generation of the present invention, comprises " opening " and " pass " on-off control pocket, instantaneous modifiable on-off control part;
Fig. 2 is the proteinic synoptic diagram of Fig. 1, and wherein the on-off control part is in and closes the marriage relation of on-off control pocket, thereby makes protein be the first biological downward modulation conformation;
Fig. 3 and Fig. 1 are similar, but the on-off control part is in its electric charge decorating state, and wherein the OH group of some amino-acid residue is by phosphorylation;
Fig. 4 and Fig. 2 are similar, but the on-off control part in this protein is in and open the marriage relation of on-off control pocket, thereby protein are be different from the second biological activity conformation of first conformation of Fig. 2;
Fig. 4 a is the synoptic diagram that amplifies, and has shown the on-off control part residue of phosphorylation and the combination between the complementary residue on the on-off control pocket;
Fig. 5 and Fig. 1 are similar, but illustrate that possible micromolecular compound is in and opens and close on-off control pocket bonded relation;
Fig. 6 is a kind of protein, and wherein on-off control ligand moiety and on-off control pocket have formed combination switch control pocket, and have small molecules with shown in compound pocket bonded relation;
Fig. 7 is a kind of proteinic synoptic diagram, and wherein switchgroup control pocket is that part, on-off control ligand sequence and active A TP site by the on-off control pocket forms, and have small molecules with shown in switchgroup control the pocket marriage relation.
Detailed description of the preferred embodiments
The protein (for example Mammals especially human protein) that the invention provides reasonable development and natural generation interacts with the method for the new small-molecule modulators of regulating protein active.New protein-small molecules adducts also is provided.The present invention preferably adopts the protein of natural generation, and it has a kind of conformation character, thereby protein can change their conformation in vivo according to the respective change of protein active.For example, a kind of given protein of conformation can be raised by biology, and the same protein of another kind of conformation can be reduced by biology.In addition, the present invention preferably adopts the conformational change mechanism that protein utilized of natural generation, by being called the interaction of " on-off control part " and " on-off control pocket " in the protein.
" on-off control part " is meant zone or the structural domain in the protein of natural generation here; and have one or more amino-acid residues, by biochemical modification (normally phosphorylation, sulfation, acidylate or oxidation) can be between each state instantaneous in vivo these residues of modification.Similarly, " on-off control pocket " is meant the interior many amino-acid residues that adjoin or do not adjoin of protein of natural generation, and comprise residue, residue can be in vivo in conjunction with the instantaneous modification residue that is in one kind state of switch control part, inducing or thereby the conformation of limit protein matter is regulated proteinic biological activity, thereby and/or the residue on-off control conditioning agent molecule that can produce in conjunction with non-natural to induce or to limit a kind of protein conformation and regulate proteinic biological activity.
Protein of the present invention-conditioning agent adducts comprises the protein of the natural generation with on-off control pocket and the molecule that produces at the non-natural of described on-off control pocket area and protein bound, and described molecule can be by inducing or the conformation of limit protein matter and the small part that arrives is used for regulating described proteinic biological activity.Preferably, described protein also contains corresponding on-off control part, described part interacts to regulate protein conformation and biological activity with described pocket in vivo, described protein is first conformation and first biological activity when part-pocket interacts like this, and is second kind of different conformation and biological activity when not existing in described part-pocket interaction.
Can understand on-off control part/interactional characteristic of on-off control pocket with reference to figure 1-4.Particularly, in Fig. 1, illustrated protein 100 comprises " opening " on-off control pocket 102 and " pass " on-off control pocket 104, and on-off control ligand 1 06.In addition, illustrated protein also comprises ATP reactive site 108.In the exemplary proteins of Fig. 1, ligand 1 06 has three amino-acid residues with side chain OH group 110.Close pocket 104 and contain corresponding X residue 112, open-bag 102 has Z residue 114.In exemplary example, protein 100 will change its conformation according to the state of charge of 0H group 110 on the ligand 1 06, promptly present neutral charge when the 0H group is modified, but present negative charge during by phosphorylation when these groups.
Can understand the function of pocket 102,104 and ligand 1 06 with reference to figure 2-4.In Fig. 2, ligand 1 06 interacts with closing pocket 104 operability, thus the part of 0H group 110 and X residue 112 interactions formation pocket 104.This interaction mainly is because the hydrogen bond between OH group 110 and the residue 112.As shown in the figure, this part/pocket interacts and protein 100 is be different from conformation seen in fig. 1, and consistent with proteinic pass conformation or biological downward modulation conformation.
Fig. 3 illustrates that ligand 1 06 removes simultaneously OH group 110 from pass pocket interaction conformation shown in Figure 2 and give the state of this part negative charge by phosphorylation.In this state, this part has intensive and open-bag 102 interactional tendencies, thereby protein conformation is changed over out state or biological rise state (Fig. 4).Thereby the phosphorylation group on Fig. 4 a explanation ligand 1 06 combines with positive charge residue 114 and forms the stable key of ion sample.Notice that opening in the conformation of Fig. 4, protein conformation is different from the pass conformation of Fig. 2, and can obtain the ATP reactive site, and protein has kinase function.
Fig. 1-4 explanation protein shows discontinuous pocket 102 and 104 and the simple state of ligand 1 06.Yet, observe complicated more on-off control pocket pattern as a rule.In the state shown in Figure 6, formed and the interactional suitable pocket of small molecules by ligand 1 06 and for example amino-acid residue of pocket 102." combination switch control pocket " (composite switch control pocket) is defined as being made of the residue of ligand 1 06 and pocket, and represents with numeral 120.For the purpose that protein is regulated, small molecules 122 interacts with pocket 120.
Fig. 7 has described another complicated more switch pocket, and wherein pocket comprises the residue of open-bag 102 and " switchgroup control pocket " (combined switch control pocket) that ATP site 108 is called with formation.This combination pocket is represented with numeral 124, also can be comprised the residue of ligand 1 06.For the purpose that protein is regulated, suitable small molecules 126 combines with pocket 124.
Should be appreciated that in the simple pocket state shown in Fig. 1-4, small molecules will interact with simple pocket 102 or 104, in the complicated more state shown in Fig. 6 and 7, the interaction pocket is in pocket 120 or 124 zones.Therefore, in general, small molecules " in each on-off control pocket area " interacts.
Material and method
The general of compound synthesized
In this a part of synthetic schemes, q is 0 or 1.When q=0, the non-interference radicals R that substituting group is synthesized
7Replace.
According to the synthetic route shown in the scheme 1.1, preparation I compound, wherein Q takes from Q-1 or Q-2, and Y is an alkylidene group.Lsothiocyanates 1 and chlorine reaction add isocyanic ester 2 subsequently, obtain 3-oxygen-thiadiazoles salt 2.With air quencher reaction, obtain the compound of formula 1-4.Perhaps, lsothiocyanates 1 reacts under reaction conditions with lsothiocyanates 5, obtains the compound of formula I-7.Referring to A.Martinez etc., Journal of MedicinalChemistry (2002) 45:1292.
Intermediate 1,2 and 5 can be buied, or according to scheme 1.2 preparations.Amine 8 and phosgene or the reaction of phosgene equivalent obtain isocyanic ester 2.
Similarly, according to the S.Buchwald reported method, amine 8 obtains lsothiocyanates 5 with the thiophosgene reaction.Amine 8 makes by palladium (O)-catalytic amination 9, and wherein M is the group that palladium (O) is inserted in the energy oxidation.Referring to M.Wolter etc., Organic Letters (2002) 4:973; B.H.Yang and S.Buchwald, Journal ofOrganometallic Chemistry (1999) 576 (1-2): 125.In this response hierarchy, P is suitable amine protecting group.Employing is at document " protecting group in the organic synthesis " (Protective Groups in OrganicSynthesis, Peter G.M.Wutts, the 3rd edition (in April, 1999) Wiley of Theodora Greene (volume), John﹠amp; SOns, Incorporated; ISBN:0471160199) amine protecting group is used and removed to reported method in.Starting compound 9 can be buied, or easily make by those skilled in the art: referring to " the senior organic chemistry of MarchShi: reaction, mechanism and structure " (March ' s Advanced Organic Chemistry:Reactions, Mechanismsand Structure), Michael B.Smith ﹠amp; The 5th edition (January calendar year 2001) Wiley John﹠amp of Jerry March (volume); SOns; ISBN:0471585890.
Scheme 1.1
Scheme 1.2
Can also obtain formula I compound by the synthetic route shown in the scheme 1.3, wherein Q takes from Q1 or Q-2, and Y is an alkylidene group.Amine 8 and isocyanic ester or lsothiocyanates 2a reaction produce urea/thiocarbamide 8a, can be by adding the cyclisation of chloroformyl sulfenyl chlorine.Further details is referring to GB1115350 and US3818024, JOC 1972,37 (10), 1532 such as United States Patent (USP)s such as Revankar 4,093,624 and Klayman.Wherein, R
4Be the protecting group (as R=3, the 4-d-methoxybenzylamine) of easily removing, the effect of gentle acid deprotection condition such as CAN or TFA discloses female member ring systems of I-4 (X=O) and I-7 (X=S).
Scheme 1.3
Shown in scheme 1.4, also can obtain I-7.Isocyanic ester or lsothiocyanates 2a and amine R
5NH
2Condensation produces urea/thiocarbamide 2b, according to GB1115350 and US3818024, when reacting with chloroformyl sulfenyl chlorine, produces 2c.R wherein
4Be the protecting group (as R=3, the 4-d-methoxybenzylamine) of easily removing, the effect of mild acidic conditions such as CAN or TFA discloses female member ring systems of 2d.2d and NaH react in DMF, and displacement, and wherein M is suitable leaving group, and as muriate, bromide or iodide produce I-4 (X=O) and I-7 (X=S).
Scheme 1.4
By the synthetic route shown in the scheme 1.3, can obtain formula I compound, wherein Q takes from Q-1 ' or Q-2 ', and Y is an alkylidene group.Isocyanic ester or lsothiocyanates 2a and ammonia condensation produce urea/thiocarbamide 2e, according to GB1115350 and US3818024, when they during with the reaction of chloroformyl sulfenyl chlorine, generation 2f.2f and NaH react in DMF and replace, and wherein M is suitable leaving group, as muriate, bromide or iodide, produce I-4 ' (X=O) and I-7 ' (X=S).
Scheme 1.5
According to the synthetic route shown in scheme 2.1 and 2.2, can obtain formula I compound respectively, wherein Q takes from Q-3 or Q-4, and Y is an alkylidene group.12 (wherein M is suitable leaving group) are reacted with the hydrazine 13 that carbamate is protected, and obtain intermediate 14.14 and isocyanate reaction, obtain intermediate 15.15 thermal cyclizations obtain 1,2 of formula I-36,4-triazolidine diketone.Draw analogous conclusions, 3-sulphur-5-oxygen-1,2 of scheme 2.2 formula I-18, the 4-triazolidine is by intermediate 14 and lsothiocyanates reaction, and thermal cyclization makes subsequently.
Scheme 2.1
Scheme 2.2
Wherein p is that 1 intermediate 12 obtains easily, or reacts acquisition by 19 with carbamate 10 under palladium (O)-catalytic condition.M
1Being the group that palladium (O) is inserted in oxidation, better is the group of iodine or bromine, and reactive behavior is greater than M.Compound 19 can be buied or be prepared by those skilled in the art.
Scheme 2.3
Also can be according to the synthetic route preparation I compound shown in the scheme 2.4, wherein D takes from Q-3 or Q-4, and Y is an alkylidene group.Amine R
4NH
2Be oxidized to corresponding hydrazine, with the chloro-formic ester condensation, postheating produces 1,2,4-triazolidine diketone 15a.After the NaH effect in DMF, displacement produces I-16 (X=O) and 1-18 (X=S), and wherein M is suitable leaving group, as muriate, and bromide or iodide.
Scheme 2.4
Also can be according to the synthetic route preparation I compound shown in the scheme 2.4, wherein D takes from D-3 ' or D-4 ', and Y is an alkylidene group.Work as R
5When being the protecting group (as R=3, the 4-d-methoxybenzylamine) of easily removing, to the gentleness of 15a, the effect of acid deprotection condition such as CAN or TFA discloses 1,2,4-triazolidine diketone 15b.15b by NaH deprotection among the DMF after, displacement produce 1-16 ' (X=O) and I-18 ' (X=S), wherein M is suitable leaving group, as muriate, bromide or iodide.
Can be according to the synthetic route preparation I compound shown in the scheme 3, wherein Q takes from Q-5 or Q-6, and Y is an alkylidene group.Hydrazine 20 and chloro sulfonyl isocyanate and alkali such as triethylamine react, and obtain the mixture of intermediate 21A and 21B, and they can not separate, but can carry out cyclisation in position, obtain the compound of formula I-22A and I-22B.Compound I-22A can separate by chromatography or fractional crystallization with I-22B.Randomly, Compound I-22A and I-22B can with pure R
4OH carries out the Mitsunobu reaction, obtains the compound of formula I-23A and I-23B.Compound 20 prepares by the acid catalysis deprotection of the t-butyl carbamate of structure 14, wherein R
10It is the tertiary butyl.
Scheme 3
Preparation I compound shown in scheme 4, wherein Q is Q-7, Y is an alkylidene group.Amine 8 and maleimide 24 reactions, wherein M is suitable leaving group, obtains the compound of formula I-25.Compound 26, wherein M is the group of oxidable insertion Pd (O), can participate in reacting with the Heck of maleimide 27, obtains the compound of formula I-28.Maleimide 24 and 27 can be buied, or is prepared by those skilled in the art.
Scheme 4
According to M.Tremblay etc., Journal of Combinatorial Chesmistry (2002) 4:429 reported method, preparation I compound shown in scheme 5, wherein Q is Q-8, Y is an alkylidene group.The Acibenzolar 29 of polymkeric substance combination (polymer bonds is the oxime Acibenzolar) and chloro sulfonyl isocyanate and trimethyl carbinol reaction obtain N-BOC sulfonylurea 30.Make 30 and R
4OH carries out the Mitsunobu reaction, obtains 31.The BOC-base is with sour, and better trifluoroacetic acid is removed, and uses alkali then, and better triethylamine is handled, and obtains required sulfahydantoin 1-32.Randomly, the acid of intermediate 30 usefulness, better trifluoroacetic acid is handled, and obtains the unsubstituted sulfahydantoin 1-33 of N-.
Scheme 5
Can also be by shown in the scheme 5a, preparation I compound, wherein Q is Q-8, Y is an alkylidene group.Amine 8 and the condensation of oxalic dialdehyde half ester produce 31a.Chloro sulfonyl isocyanate at first with benzylalcohol, then with 31a reaction, produce 31b, the heating back produces I-32.
Scheme 5a
According to the synthetic route preparation I compound shown in the scheme 5.2, wherein Q takes from Q-8 '.Method by Muller andPuBois JOC 1989,54,4471 forms 31c, with NaH/DMF or NaH/DMF deprotection, alkylation subsequently, produces I-32 ', and wherein M is suitable leaving group, as muriate, and bromide or iodide.Perhaps, can also shown in scheme 5.3, obtain I-32 '.The Mitsunobu reaction of boc-sulphonamide amino ethyl ester and pure 8b (by being similar to the preparation of the method for amine 8) produces 31c, with removing behind the Boc by the effect cyclisation of NaH to 31d generation I-32 ' in the 2N HCL Zai diox.
Scheme 5.2
Scheme 5.3
Preparation I compound shown in scheme 6, wherein Q is Q-9, Y is an alkylidene group.The amino acid ester 34 and the isocyanate reaction of polymkeric substance combination obtain intermediate urea 35.Using alkaline purification, better is that pyridine or triethylamine handle 35, can select heating, obtains the compound of formula I-36.
Scheme 6
Also can be shown in scheme 6.1 preparation I compound, wherein Q is Q-9, Y is an alkylidene group.Aldehyde 8c under the reduction amination condition with the reaction of the tert-butyl ester of glycerine, produce 35a.Isocyanic ester 2a and p-NP (or corresponding R
4NH
2Amine and p-nitrophenyl chloroformate ester condensation) condensation, produce the carboxylamine p-nitrophenyl ester, when the 35a with deprotection reacts, produce urea, produce 35b during with sour deprotection.Formula I-36 can directly be obtained by 35b by NaH effect and heating.
Scheme 6.1
According to the synthetic route preparation I compound shown in the scheme 6.2, wherein Q takes from Q-9 '.Adopt JP10007804A2 and Zvilichovsky and Zucker; Israel Journal of Chemistry; 1969,7 (4), the described method of 547-54 forms 35c; and with NaH/DMF or NaH/DMF deprotection; with rear substitution M, wherein M is suitable leaving group, as muriate; bromide or iodide produce I-36 '.
Scheme 6.2
Respectively as described in scheme 7.1 and 7.2, preparation I compound, wherein, Q is Q-10 or Q-11, Y is an alkylidene group.Alcohol 37 (Z=O) or amine 37 (Z=NH) are handled with chloro sulfonyl isocyanate, obtain the intermediate carbamate or the urea of structure 38.38 usefulness structure HN (R
4)
2Amine and alkali, better triethylamine or pyridine are handled, and obtain the sulfonylurea of formula I-39.Chloro sulfonyl isocyanate and alcohol (Z=O) or amine (Z=NR
4) 40 reactions, obtain intermediate 41.41 usefulness amine 8 and alkali, better triethylamine or pyridine are handled, and obtain the sulfonylurea of formula I-42.
Scheme 7.1
According to the synthetic route preparation I compound shown in the scheme 8, wherein, Q takes from Q-12.Pyridine 43, wherein TIPS is three-sec.-propyl silyl, (K under standard conditions
2CO
3, DMF, R
4-I or use R
4The Mitsunobu condition of-OH) alkylation produces pyridine derivate 44, this derivative and compound 12 reactions, and the pyridone of acquisition formula I-45, wherein M is suitable leaving group.
Scheme 8
According to the synthetic route preparation I compound shown in the scheme 9, wherein, Q takes from Q-13.From facile pyridine 46, alkylation (K under standard conditions
2CO
3, DMF, R
4-I or use R
4The Mitsunobu condition of-OH) produces pyridine derivate 47.Use K
2CO
3, DMF, R
4-I carries out the N-alkylation, the pyridone of acquisition formula 48.Distribute intermediate 48 to carry out the Heck reaction, obtain I-49; The Buchwald amination reaction obtains I-51; Or the reaction of Buchwald Cu (I) catalysis O-arylation, obtain I-52.Randomly hydrogenation of Heck reaction product I-49 obtains saturated compound I-50.Phenylate R wherein
4Group is a methyl, formula I-49, and I-50, I-51 or I-52 compound are handled with boron tribromide or lithium chloride, obtain formula I-53 compound, wherein R
4Be hydrogen.
Scheme 9
According to the synthetic route preparation I compound shown in the scheme 9, wherein, Q takes from Q-14.From facile pyridine 54, alkylation (K under standard conditions
2CO
3, DMF, R
4-I or use R
4The Mitsunobu condition of-OH), produces pyridine derivate 55, use K
2CO
3, DMF, R
4-I carries out alkylation, the pyridone of acquisition formula 56.Distribute intermediate 56, wherein M is suitable leaving group, better is bromine or chlorine, carries out the Heck reaction, obtains I-57; The Buchwald amination reaction obtains I-59; The reaction of Buchwald Cu (I) catalysis O-arylation obtains I-60.Heck reaction product I-57 can also be optionally hydrogenated, obtains saturated compound I-58.R wherein
4Be methyl, formula I-57, I-58, the compound of I-59 or I-60 is handled with boron tribromide or lithium chloride, obtains formula I-61 compound, wherein R
4Be hydrogen.
Scheme 10
Synthetic route preparation I compound shown in scheme 11 and 12, wherein, Q takes from Q-15.Initial ester 62 can form by TBS-ether and ester under the standard conditions, is obtained by corresponding department theobromine (secoacid).But department's ester (secoester) 62 of protection produces vinyl ether 63 as a pair of regional isomer (regioisomer) with the Meerwin reactant salt.Perhaps, 62 obtain vinylogue carbamate 64 with dimethylamine reaction.65 close by contracting with urea, azeotropic is removed dimethylamine or methyl alcohol, forms dihydro-pyrimidin diketone 66.Dihydro-pyrimidin diketone 66 can be randomly by the Mitsunobu reaction, further by pure R
40H replaces, and obtains compound 67.
The further synthetic intermediate 67 of scheme 12 explanations.67 usefulness fluorochemicals (fluoridizing four positive fourth ammonium or cesium fluorides) are handled, and reach and remove silyl protecting group (TBS), obtain primary alconol 68.68 with isocyanic ester 2 reaction, obtain formula I-69 compound.Perhaps, 68 with [R
602C (NH)
p]
q-D-E-M reaction, wherein M is suitable leaving group, obtains the compound of formula I-70.Use high iodine alkane of Dess-Martin (periodinane) (D.Dess, J.Martin, J.A711.Chem.SOc. (1991) 113:7277) or four positive alkyl peruthenate (W.Griffith, S.Ley, Aldrichimica Acta (1990)
23:13) oxidation 68, obtain aldehyde 71.71 usefulness amine, 8 reduction aminations obtain the compound of formula I-72.Perhaps, aldehyde 71 reacts under the reductive alkylation condition with ammonium acetate, obtains primary amine 73.73 with the compound of isocyanic ester 2 reaction acquisition formula I-74.
Scheme 11
Scheme 12
According to the synthetic route preparation I compound shown in scheme 13 and 14, wherein, Q takes from Q-16.Initial ester 75 can be obtained by corresponding department theobromine by the formation of TBS-ether under standard conditions and ester.But shielded department ester 75 and Meerwin reactant salt produce vinyl ether 76, as a pair of regional isomer.Perhaps, 75 with dimethylamine reaction, obtain vinylogue carbamate 77.By with urea 65 condensations, azeotropic is removed dimethylamine or methyl alcohol, forms dihydro-pyrimidin diketone 78.Dihydro-pyrimidin diketone 78 also randomly further reacts by pure R by Mitsunobu
40H replaces, and obtains compound 79.Formula I-81, I-82, the compound of I-84 and I-86 can be according to shown in the scheme 14, by being similar to the order preparation described in the front scheme 12.
Scheme 13
Scheme 14
Acetacetic acid alkyl ester 87 can be buied, and can be converted into ester 88 shown in scheme 15.In THF, handle 87 with NaHMDS, use formaldehyde and TBSC subsequently
1(n=1) or Q-(CH
2)
n-OTBS (n=2-4) quencher obtains compound 88.
Scheme 15
According to the synthetic route preparation I compound shown in scheme 16.1 and 16.2, wherein, Q takes from Q-17; hydrazine 13 beginnings with the BOC-protection; this hydrazine passes through the reductive alkylation with the glyoxal derivative of sodium cyanoborohydride and acid extraction (workup) mediation, is converted into 1, and 2-two replaces hydrazines 89.Reflux down, 89 with diethyl malonate condensation in benzene, produce heterocycle 90.Use N
204Oxidation in benzene (referring to Cardill, Merlini and Boeri Gazz.Chim.Ital., (1966) 9:8) is a nitro malonyl-hydrazine 91, and uses P
205In benzene, further handle (referring to: Cardillo, G. etc., Gazz.Chim.Ital. (1966) 9:973-985), produce three carbonyls 92.Perhaps, 90 usefulness Brederick reagent (t-BuOCH (N (Me
2)
2Handle, obtain 93, carry out ozone and decompose,, obtain three carbonyls 92 of protection with DMS and methanol extraction.Compound 92 at the easy deprotection of THF effect, produces primary alconol 94 by CsF.Form by the order tosylate, the trinitride displacement and and hydrogenation, alcohol 94 can be chosen wantonly and be converted into primary amine 95.
Scheme 16.1
Under copper (I) catalysis, 94 with (mix) aryl halide 26 reaction, wherein M is an iodo, bromo or chloro, acquisition Compound I-96.To the optional deprotection of dimethyl ketal, obtain the compound of formula I-98 with aqueous acids.Draw analogous conclusions, amine 95 and 26 reacts under palladium (0) catalysis, obtains the compound of formula I-97.To the optional deprotection of dimethyl ketal, obtain the compound of formula I-99 with aqueous acids.
Scheme 16.2
According to the synthetic route preparation I compound shown in the scheme 16.3, wherein, Q takes from Q-17.With NaH/DMF or NaH/DMF to 4,4-dimethyl-3,5-dioxy-pyrazolidine (95a; according to Zinner and Boese, D.Pharmazie1970,25 (5-6); 309-12 and Bausch, J.Org.Chem.1991 such as M.J., 56 (19); 5643 described method preparations) deprotection; with rear substitution M, wherein M is suitable leaving group, as muriate; bromide or iodide produce I-99a.
Scheme 16.3
Preparation I compound shown in scheme 17.1 and 17.2, wherein, Q takes from Q-18.Amino ester 100 is carried out reductive alkylation, obtains intermediate 101.Use acid activators such as dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOBt), amine 101 and carboxylic acid condensation obtain midbody acid amide 102.After capturing alkoxide 103 that original position produces and 103 resins that pass to the acetate mediation being discharged, can be tetrameric acid 104 by 102 cyclisation of Amberlyst A-26 oxyhydroxide resin mediation acid amides.
Scheme 17.1
Scheme 17.2 explanations are converted into intermediate 104 the synthetic order of formula I compound.Alcohol 104.1 reacts under copper (I) catalysis with aryl halide or heteroaryl halogenide 26 (Q=halogen), obtains the compound of formula I-105.1.Amine 104.2 and 104.3 and 26 reacts under Buchwald palladium (O) Study on Catalytic Amination of Alcohols condition, obtains the compound of formula I-105.2 and I-105.3.Acetylene 104.4 and 26 reacts under the SOnogashira coupling condition, obtains formula I-105.4 compound.Compound I-105.4 can be chosen wantonly by standard hydrogenation and be reduced to corresponding saturated analogues I-105.5.
Scheme 17.2
According in scheme 18 preparation I compound being described, wherein, Q takes from Q-19, Q-20 or Q-21.Use dewatering agent, better DIC (DIC) or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC), the Kemp acid 106 that can buy is converted into its acid anhydride 107.107 with amine R
4NH
2Reaction obtains midbody acid amide, and this acid amides can be by reacting with DIC or EDC, and cyclisation is an imide 108.Perhaps, 107 with amine 8 reaction, obtain formula I-110 acid amides.Acid amides I-110 also can choose wantonly and DIC or EDC reaction, obtains the compound of formula I-111.Acid 108 is further reacted with amine 8, obtains the compound of formula I-109.
Scheme 18
By preparation I compound shown in the scheme 19.1 to 19.3, wherein, Q takes from Q-22 or Q-23.Shown in scheme 19.1, by dihalo (mixing) aryl 112 preparation intermediates 113 and 114, wherein M2 is the leaving group stronger than M1.112 with amine 37 (Z=NH) thermal response in the presence of alkali, or, in the presence of alkali and phosphine part, react acquisition compound 113 by palladium (O) catalysis.Perhaps, 112 with alcohol 37 (X=O) thermal response in the presence of alkali, or, in the presence of alkali, react acquisition compound 114 by copper (I) catalysis.
Scheme 19.1
Scheme 19.2 explanation intermediates 113 are converted into formula I-115, I-118 or 117 compounds.Oxidizing aqueous copper of 113 usefulness or alkaline hydrated oxide are handled, and obtain the compound of formula I-115.Perhaps, under copper (I) catalysis, in the presence of ethylene glycol and salt of wormwood, 113 usefulness tert-butyl mercaptans are handled, and obtain 116 (referring to F.Y.Kwong and S.L.Buchwald, Organic Letters (2002) 4:3517).Tertiary butyl sulphur 116 and acid-respons obtain the mercaptan of required formula I-118.Perhaps, 113 usefulness excess ammonia are handled under pressurized conditions, obtain compound 117.
Scheme 19.2
Scheme 19.3 explanation is adopted and is similar to the order described in the scheme 19.2, and intermediate 114 is converted into formula I-119, I-122 and 121 compound.
Scheme 19.3
By preparation I compound shown in the scheme 20, wherein, Q takes from Q-24, Q-25 or Q-26.Compound I-115 or I-119 and chloro sulfonyl isocyanate reaction are subsequently by original position and amine HN (R
4)
2React, obtain the compound of formula I-123 or I-124.Compound I-118 or I-122 and peracid, better peracetic acid or trifluoroperacetic acid reaction, the compound of acquisition formula I-125 or I-126.Compound 117 or 121 and chloro sulfonyl isocyanate reaction, original position and amine HN (R subsequently
4)
2Or pure R
40The H reaction obtains formula I-127, I-128, the compound of I-129 or I-130.
Scheme 20
According to the explanation preparation I compound in the scheme 21, wherein, Q takes from Q-27.Parathiazan obtains benzylamine 132 with aldehyde 131 reductive alkylations, carries out acid oxidase then, obtain parathiazan sulfone 133 (referring to C.R.JohnSOn etc., Tetrahedron (1969)
25:5649).Intermediate 133 and amine 8 (Z=NH
2) under Buchwald palladium-Study on Catalytic Amination of Alcohols condition, react, obtain the compound of formula I-134.Perhaps, compound 133 reacts under Buchwald copper (I) catalytic condition with alcohol 8 (Z=OH), obtains the compound of formula I-135.Perhaps, intermediate 133 reacts under palladium (O)-catalytic Heck reaction conditions with alkene, obtains the compound of formula I-136.Compound I-136, is chosen wantonly and is reduced to corresponding saturated analogues I-137 under the imide effect by the standard hydrogenation conditions.
Scheme 21
Also as in the scheme 21.1 preparation I compound being described, wherein, Q takes from Q-27.Aldehyde 8c can with the ammonia reductive amination, the amine of generation and divinylsulfone condensation produce I-134.Intermediate 134a also can obtain by reducing amide 8d under various standard conditions.
Scheme 21.1
More at large, shown in scheme 12.2, amine 134c can obtain by the reduction of acid amides 134b.By shown in the scheme 21.1, also can obtain morpholine amide analogue 134d and morpholine analogue 134e.
Scheme 21.2
According to the order preparation I compound of scheme 22 explanations, wherein, Q takes from Q-28 or Q-29.Facile acid amides 138 and chloro sulfonyl isocyanate reaction obtain intermediate 140, its original position and amine HN (R
4)
2Or pure R
40H reacts, and obtains the compound of formula I-141 or I-142 respectively.Perhaps, acid amides 138 and SULPHURYL CHLORIDE reaction, the compound of acquisition formula I-139.
Scheme 22
According to preparation I compound shown in the scheme 23, wherein Q takes from Q-30.Facile N-BOC acid anhydride 143 (referring to S.Chen etc., J.Am.Chem.SOc. (1996) 118:2567) and amine HN (R
4)
2Or pure R
6The OH reaction obtains acid 144 or 145 respectively.Intermediate 144 or 145 further with amine HN (R
4)
2At acid activators, better there are reaction down in PyBOP and diisopropylethylamine, obtain diamide 146 or ester-acid amide 147.Intermediate 145 by with alkyl iodide at alkali, better salt of wormwood exists down that reaction is converted into diester 148.Intermediate 146-148 handles with the HCL/ diox, obtains secondary amine 149-151, then with acid 152 condensations in the presence of PyBOP and diisopropylethylamine, obtains the compound of formula I-153.
Scheme 23
According to the order of scheme 24 explanations, preparation I compound, wherein Q takes from Q-31 or Q-32.Facile sulfinyl amine 154 usefulness amine 37 (Z=NH), alcohol 37 (Z=O) or alkene 37 (Z=-CH=CH
2) handle, obtain the compound of formula I-155.Sulfinyl amine I-155 uses iodosobenzene at pure R
4OH exists down and handles, and obtains the sulfo group imido-ester (referring to D.Leca etc., Organic Letters (2002) 4:4093) of formula I-157.Perhaps, Compound I-155 (Z=-CH=CH) can be chosen wantonly and be reduced to saturated analogues I-156 (Z=CH
2-CH
2-), they are converted into corresponding sulfo group imido-ester I-157.
Facile SULPHURYL CHLORIDE 154.1 usefulness amine HN (R
4)
2And alkaline purification, obtain the compound of formula I-154.2.
Scheme 24
According to preparation I compound shown in the scheme 25, wherein Q takes from Q-33.Facile nitrile 158 and amine 37 (Z=NH), alcohol 37 (Z=O) or alkene 37 (Z=-CH=CH
2) compound of reaction acquisition formula I-159.By standard catalytic hydrogenation condition, optional its saturated analogues I-160 that is reduced to of Compound I-159 (wherein Z=CH=CH-).Compound I-159 or I-160 handle with metal azide (better sodiumazide or azide zinc), obtain the tetrazolium of formula I-161.
Scheme 25
Shown in scheme 26, preparation I compound, wherein Q takes from Q-34.Facile ester 162 and amine 37 (Z=NH), alcohol 37 (Z=O) or alkene 37 (Z=-CH=CH
2) compound of reaction acquisition formula I-163.By the standard hydrogenation conditions, (wherein Z is-CH=CH-) the optional saturated analogues I-164 that is converted into Compound I-163.By relating to ester reduction is benzylalcohol, and this alcohol is converted into bromotoluene, the Arbuzov response hierarchy that this bromide is handled with trialkyl phosphite, and Compound I-163 or I-164 are converted into required phosphonic acid ester I-165.Perhaps, logical the begging for diethylaminosulfur trifluoride (DAST) processing of phosphonic acid ester I-165 is converted into fluorinated analogues-166.
Scheme 26
According to scheme 27 preparation I compounds, wherein Q takes from Q-35.Facile chloride of acid 167 Yu oxazolidinediones react in the presence of alkali, obtain N-Xian oxazolidinone 168.Intermediate 168 and amine 37 (Z=NH), alcohol 37 (Z=O) or alkene 37 (Z=-CH=CH
2) reaction, the N-Xian oxazolidinone of acquisition formula I-169.Under the standard hydrogenation conditions, (wherein Z is-CH=CH-) the optional saturated analogues I-170 that is converted into Compound I-169.
Scheme 27
By scheme 27.1 described preparation I compounds, wherein Q takes from Q-35.Intermediate 8a, M wherein are suitable leaving group such as muriates, and bromide or iodide reflux with triethyl phosphine, and phosphoryl intermediate saponification under mild conditions of generation produces I-165.
Scheme 27.1
According to scheme 28.1 and 28.2 described preparation I compounds, wherein Q takes from Q-36.The piperazine that tertiary butyl sulphur replaces obtains benzyl diethylenediamine 171 with facile aldehyde 131 reductive alkylations.Intermediate 171 and amine 37 (Z=NH), alcohol 37 (Z=O) or alkene 37 (Z=-CH=CH
2) reaction, obtain compound 172,173 or 174 respectively.Perhaps, intermediate 174 is converted into saturated analogues 175 under the standard hydrogenation conditions.
Scheme 28.1
Scheme 28.2 explanation intermediate tertiary butyl sulphur 172-175 are converted into sulfonic acid; adopt two-step approach; the acid catalysis deprotection that relates to tertiary butyl sulphur is corresponding mercaptan, and crosses the sulfonic acid that acid oxidase (more handy peracetic acid or difluoro peracetic acid) mercaptan is required formula I-176 subsequently.
Scheme 28.2
In some cases, Z=NH, O, CH=CH, CH
2-CH
2Preparation heterocomplex p38-alpha kinase inhibitor, this inhibitor also contains ATP-pocket bound fraction or allosteric pocket bound fraction R
1-X-A.Formula R
1The functionalization of-X-A intermediate is synthetic can be finished shown in scheme 29.Facile intermediate 177 contains the group M that the energy oxidation adds to palladium (O), and this intermediate and amine 178 (X=NH) is thermal response under Buchwald Pd (O) amination condition, obtains 179.Perhaps, amine or alcohol 178 (X=NH or O) and 177 react under nuclear aromatics substitution reaction condition in the presence of alkali, obtain 179.Perhaps, alcohol 178 (X=O) and 177 reactions under Buchwald copper (I)-catalytic condition obtain 179.The situation of p=1 is removed 179 carbamate therein, under the sourer condition, works as R
6When being the tertiary butyl, obtain amine 180.The situation of p=0 wherein, ester 179 are converted into acid 181, under the sourer condition, work as R
6When being the tertiary butyl.
Scheme 29
Scheme 30 explanation preparation amine 180 in addition-kind of order.Amine or alcohol 178 and 182 reactions of nitro (mixing) aromatic hydrocarbons, wherein M is a leaving group, better M is that fluorochemical or M are the groups that palladium (O) is inserted in the energy oxidation, the bromo of better M, chloro or iodo obtain intermediate 183.Nitro reduces or uses the reducing metal under the standard hydrogenation conditions, handle as tin protochloride, obtains amine 180.
Scheme 30
During preparation hybrid p38-alpha kinase inhibitor, adopt and be similar to scheme 29 described conditions, formula I-184 compound, wherein Q is 1, can be converted into amine I-185 (p=1) or sour I-186 (p=0).According to scheme 1.1,2.1,2.2,3,4,5,6,7.1,7.2,8,9,10,12,14,16.2,17.2,18,19.1,19.2,19.3,20,21,22,23,24,25,26,27 or 28.2 is described, the compound of preparation formula I-184.
Scheme 31
Compound I-184 comes from scheme 1.1,2.1,2.2,3,4,5,6,7.1,7.2,8,9,10,12,14,16.2,17.2,18,19.1,19.2,19.3,20,21,22,23,24,25,26,27,28.2
Scheme 32 is depicted as the inhibitor of preparation formula I, and described inhibitor contains and connects oxygen anion (oxyanion) pocket bound fraction and R
1Amido linkage-the CO-NH-of-X-A part.Using activator, better is PyBOP, handles acid 181 in the presence of two-sec.-propyl ethamine and amine 1-185, obtains formula I compound.Perhaps, the anti-acid amides of formula I can form by handle sour I-186 in the presence of two-sec.-propyl ethamine and amine 180 with PyBOP.
Scheme 32
Be preparation formula I inhibitor shown in the scheme 33, inhibitor contains and connects oxygen anion pocket bound fraction and R
1The urea key NH-CO-NH-of-X-A part.With p-nitrophenyl chloroformate ester and alkaline purification amine I-185, obtain carbamate 187.187 with amine 180 reaction, obtain the urea of formula I.
Scheme 33
Formula I
(the heterozygosis inhibitor has the oxygen anion mouth
Bag bound fraction Q and part R1-X-A)
Perhaps, by the inhibitor of preparation formula I shown in the scheme 33, inhibitor contains and connects oxygen anion pocket bound fraction and R
1The urea key NH-CO-NH-of-X-A part.With p-nitrophenyl chloroformate ester and alkaline purification amine 180, obtain carbamate 188.188 with amine I-185 reaction, obtain the urea of formula I.
Scheme 34
Formula 1
(the heterozygosis inhibitor has the oxygen anion mouth
Bag bound fraction Q and part R1-X-A)
The avidity and the biological assessment of P38-alpha kinase inhibitor
As previously described, adopt fluorescence in conjunction with testing the combination of measuring formula I inhibitor with unphosphorylated P38-alpha kinase: referring to J.Regan etc., Jozcnaal of Medicinal Chemistry (2002) 45:2994.
1.P38 map kinase is in conjunction with mensuration
Adopt SKF 86002 as the fluorescent probe competition experiments, mensuration is to the binding affinity of the kinase whose small-molecule modulators of p38MAP, improve (C.Pargellis according to open method, Deng Nature StructuralBiology (2002) 9,268-272.J.Regan, Deng J.Med.Chem. (2002) 45,2994-3008).Briefly, SKF 86002, and the kinase whose protein inhibitor of p38 (Kd=180nM) when it is attached to kinases when 340nm is excited, is launched the fluorescence of about 420nm.Therefore, inhibitor can be measured from the ability of SKF86002 fluorescence by its reduction the kinase whose binding affinity of p38.This is determined at one 384 plate (opaque 384 plates of Greiner), carries out on PolarstarOptima plate reader (BMG).Usually, reaction mixture contains 1 μ M SKF 86002, the inhibitor of 80nM p38 kinases and different concns, and in 20mM Bis-Tris propane damping fluid, pH 7, contain 0.15% (w/v) n-octyl glucoside and 2mM EDTA, in 65 μ l final volumes.Cause this reaction by adding enzyme.Plate reads out in the emission of 420nm and exciting at 340nm afterwards room temperature (about 25 ℃) hatching 2 hours.Compare rfu (relative fluorescence unit) value and the value that contrasts (not having inhibitor), calculate the inhibition percentage ratio of each inhibitor concentration.The IC of inhibitor
50Value is by using Prism, the inhibition % value calculating that obtains in the concentration range of inhibitor.When the evaluation time-dependent manner suppresses, a plurality of reaction times as 0.5,1, read flat board in 2,3,4 and 6 hours.Calculate IC at each time point
50Value.If IC
50Value descended (in 4 hours greater than 2 times) with the reaction times, and inhibition is determined as time-dependent.
| Embodiment | IC 50，nM | Time-dependent |
| 1 | 292 | Be |
| 2 | 997 | Not |
| 3 | 231 | Be |
| 4 | 57 | Be |
| 5 | 1107 | Not |
| 6 | 238 | Be |
| 7 | 80 | Be |
| 8 | 66 | Be |
| 9 | 859 | Not |
| 10 | 2800 | Not |
| 11 | 2153 | Not |
| 12 | About 10000 | Not |
| 13 | 384 | Be |
| 15 | 949 | Not |
| 19 | About 10000 | Not |
| 21 | 48 | Be |
| 22 | 666 | Not |
| 25 | 151 | Be |
| 26 | 68 | Be |
| 29 | 45 | Be |
| 30 | 87 | Be |
| 31 | 50 | Be |
| 32 | 113 | Be |
| 37 | 497 | Not |
| 38 | 508 | Not |
| 41 | 75 | Be |
| 42 | 373 | Not |
| 43 | 642 | Not |
| 45 | 1855 | Not |
| 46 | 1741 | Not |
| 47 | 2458 | Not |
| 48 | 3300 | Not |
| 57 | 239 | Be |
In the THP-1 raji cell assay Raji, carry out the biological assessment of the p38-alpha kinase inhibitor of formula I, the inhibition that the TNF-α that measuring LPS-stimulates produces.Referring to J.Regan etc., Journal of Medicinal Chemistry (2002) 45:2994.
Embodiment
Following embodiment proposes the preferred method of the present invention.However, it should be understood that these embodiment only are used for explanation, do not constitute the restriction to overall range of the present invention.
[Boc-sulphamide] amino ester (reagent A A), 1,5,7-trimethylammonium-2,4-dioxy-3-aza-bicyclo [3.3.1] nonane-7-carboxylic acid (reagent BB) and Kemp acid anhydrides (reagent C C) prepare according to the method in the document.In detail referring to J.Am.Chem.SOc.1989 such as Askew, 111,1082.
Embodiment A
At 0 ℃, (add NaNO among the 200g, the solution of dense HCL 1.46mol) (200mL) at gavaculine
2(102g, aqueous solution 1.46mol) (250mL).Stirred reaction mixture 1 hour then at 0 ℃, adds SnC
122H
2(662g, dense HCL (2L) solution 2.92mol) was room temperature restir reaction 2 hours for O.Filtering precipitate with ethanol and ether washing, obtains hydrochloric acid 3-diazanyl-phenylformic acid, is white solid.
(200g, 1.06mol) with 4,4-dimethyl-3-oxygen-valeronitrile (146g, spend the night by ethanolic soln 1.167mol) (2L) reflux from the coarse raw materials that reacts previously.Vacuum-evaporation reaction soln, resistates produce 3-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) ethyl benzoate (embodiment A by column chromatography purification, 116g, 40%) be white solid together, with 3-(the 5-amino-3-tertiary butyl-1H-pyrazol-1-yl) phenylformic acid (93g, 36%).
1H NMR(DMSO-d
6)：8.09(s，1H)，8.05(brd，J＝8.0Hz，1H)，7.87(brd，J＝8.0Hz，1H)，7.71(t，J＝8.0Hz，1H)，5.64(s，1H)，4.35(q，J＝7.2Hz，2H)，1.34(t，J＝7.2Hz，3H)，1.28(s，9H).
Embodiment B
0 ℃ 1-naphthyl isocyanic ester (9.42g, 55.7mmol) and add embodiment A (8.0g, THF 27.9mmol) (200mL) solution in THF (100mL) solution of pyridine (44mL).This mixture of stirring at room 1 hour, heating is up to all solids dissolving, and restir is 3 hours under the room temperature, uses H
2O (200mL) quencher.Filtering precipitate is with rare HCL and H
2The O washing, vacuum-drying produces the 3-[3-tertiary butyl-5-(3-naphthalene-1-yl) urea groups]-the 1H-pyrazol-1-yl] ethyl benzoate (12.0g, 95%), be white powder.
1HNMR(DMSO-d
6)：9.00(s，1H)，8.83(s，1H)，8.257.42(m，11H)，6.42(s，1H)，4.30(q，J＝7.2Hz，2H)，1.26(s，9H)，1.06(t，J＝7.2Hz，3H)；MS(ESI)m/z：457.10(M+H
+)。
Embodiment C
At 0 ℃, (10.7g 70.0mmol) adds 4-nitrophenyl 4-chloro-phenyl-carbamate (10g, THF 34.8mmol) (150mL) solution in pyridine (56mL) and THF (30mL) mixture solution in embodiment A.This mixture of stirring at room 1 hour, heating is up to all solids dissolving, and restir is 3 hours under the room temperature.Add H
2O (200mL) and CH
2C
12(200mL), water phase separated is used CH
2C
12(2 * 100mL) extractions.The organic layer 1N NaOH that merges, 0.1N HCl, anhydrous Na is used in the saturated brine washing
2SO
4Dry.Solvent removed in vacuo produces the 3-{3-tertiary butyl-5-[3-(4-chloro-phenyl-) urea groups]-the 1H-pyrazol-1-yl } ethyl benzoate (8.0g, 52%).
1H NMR(DMSO-d
6)：δ9.11(s，1H)，8.47(s，1H)，8.06(m，1H)，7.93(d，J＝7.6Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.65(dd，J＝8.0，7.6Hz，1H)，7.43(d，J＝8.8Hz，2H)，7.30(d，J＝8.8Hz，2H)，6.34(s，1H)，4.30(q，J＝6.8Hz，2H)，1.27(s，9H)，1.25(t，J＝6.8Hz，3H)；MS(ESI)m/z：441(M+H
+)。
Embodiment D
At N
2Down ,-10 ℃, (8.20g adds LiAlH in THF 18.0mol) (500mL) stirred solution in Embodiment B
4Powder (2.66g, 70.0mmol).This mixture of stirring at room 2 hours is by the LiAlH of slow adding ice decomposing excessive
4With rare HCL acidified reaction mixture to pH=7, vacuum concentration, resistates extracts with EtOAc.The organic layer that vacuum concentration merges produces the 1-{3-tertiary butyl-1-[3-(methylol) phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea (7.40g, 99%), be white powder.
1H NMR(DMSO-d
6)：9.19(s，1H)，9.04(s，1H)，8.80(s，1H)，8.26-7.35(m，11H)，6.41(s，1H)，4.60(s，2H)，1.28(s，9H)；MS(ESI)m/z：415(M+H
+)。
Embodiment E
Embodiment C (1.66g, 4.0mmol) and SOC
12(0.60mL, CH 8.0mmol)
3C
1(100mL) solution refluxed 3 hours, and vacuum concentration produces the 1-{3-tertiary butyl-1-[3-chloromethyl] phenyl }-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea (1.68g, 97%), be white powder.
1H NMR(DMSO-d
6)：δ9.26(s，1H)，9.15(s，1H)，8.42-7.41(m，11H)，6.40(s，1H)，4.85(s，2H)，1.28(s，9H)。MS(ESI)m/z：433(M+H
+)。
Embodiment F
At N
2Down ,-10 ℃, (1.60g adds LiAlH in THF 3.63mmol) (200mL) stirred solution in Embodiment C
4Powder (413mg, 10.9mmol).Stirred this mixture 2 hours, by adding the excessive LiAlH of ice quenching
4Solution is acidified to pH=7 with rare HCL.Slowly remove and desolvate, cross filter solid, and wash with EtOAc (200+100mL).Concentrated filtrate produces the 1-{3-tertiary butyl-1-[3-methylol] phenyl }-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea (1.40g, 97%).
1H NMR(DMSO-d
6)：δ9.11(s，1H)，8.47(s，1H)，7.47-7.27(m，8H)，6.35(s，1H)，5.30(t，J＝5.6Hz，1H)，4.55(d，J＝5.6Hz，2H)，1.26(s，9H)；MS(ESI)m/z：399(M+H
+)。
Embodiment G
Embodiment F (800mg, 2.0mmol) and SOC
12(0.30mL, CHCL 4mmol)
3(30mL) solution refluxed 3 hours lenitively.Vacuum evaporating solvent, resistates is dissolved in CH
2C
12(in 2 * 20mL).Except that after desolvating, obtain the 1-{3-tertiary butyl-1-[3-(chloromethyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea (812mg, 97%), be white powder.
1H NMR(DMSO-d
6)：δ9.57(s，1H)，8.75(s，1H)，7.63(s，1H)，7.50-7.26(m，7H)，6.35(s，1H)，4.83(s，2H)，1.27(s，9H)；MS(ESI)m/z：417(M+H
+)。
Embodiment H
At N
2Down, 0 ℃, at LiAlH
4(5.28g, add in THF 139.2mmol) (1000mL) suspension in batches embodiment A (20.0g, 69.6mmol).Stirred reaction mixture 5 hours, in a ℃ quencher, filtering precipitate is with EtOAc washing, evaporated filtrate, generation [3-(the 5-amino-3-tertiary butyl-1H-pyrazol-1-yl) phenyl] methyl alcohol (15.2g, 89%) with 1N HCL.
1H NMR(DMSO-d
6)：7.49(s，1H)，7.37(m，2H)，7.19(d，J＝7.2Hz，1H)，5.35(s，1H)，5.25(t，J＝5.6Hz，1H)，5.14(s，2H)，4.53(d，J＝5.6Hz，2H)，1.19(s，9H)；MS(ESI)m/z：246.19(M+H
+)。
(5.0g 20.4mmol) is dissolved in anhydrous THF (50mL) and SOC to the raw material that reacts previously
12(4.85g, 40.8mmol), stirring at room 2 hours, vacuum concentration produces the 3-tertiary butyl-1-(3-chloromethyl phenyl)-1H-pyrazoles-5-amine (5.4g), and it is joined N
3(3.93g, DMF 60.5mmol) (50mL) solution.In 30 ℃ of reacting by heating mixtures 2 hours, pour H into
2Among the O (50mL), use CH
2C
12Extraction.Merge organic layer, use MgSO
4Drying, vacuum concentration produces the thick 3-tertiary butyl-1-[3-(azido methyl) phenyl]-1H-pyrazoles-5-amine (1.50g, 5.55mmol).
Example I
Embodiment H is dissolved among the anhydrous THF (10mL), add under the room temperature 1-isocyano-naphthalene (1.13g, 6.66mmol) and pyridine (5.27g, THF 66.6mmol) (10mL) solution.Stirred the mixture 3 hours, and used H
20The throw out that produces is filtered in (30mL) quencher, with 1N HCL and ether washing, produces 1-[2-(3-azido methyl-phenyl)-5-tertiary butyl-2H-pyrazole-3-yl]-3-naphthalene-1-base-urea (2.4g, 98%), be white solid.
Under 1 normal atmosphere, room temperature, raw material that reacts previously and Pd/C (0.4g) hydrogenation 2 hours in THF (30mL).Remove by filter catalyzer, vacuum concentrated filtrate produces the 1-{3-tertiary butyl-1-[3-(amino methyl) phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea (2.2g, 96%), be yellow solid.
1H NMR(DMSO-d
6)：9.02(s，1H)，7.91(d，J＝7.2Hz，1H)，7.89(d，J＝7.6Hz，2H)，7.67-7.33(m，9H)，6.40(s，1H)，3.81(s，2H)，1.27(s，9H)：MS(ESI)m/z：414(M+H
+)。
Embodiment J
Under the room temperature, embodiment H (1.50g, add in anhydrous THF (10mL) solution 5.55mmol) 4-chloro-phenyl-isocyanic ester (1.02g, 6.66mmol) and pyridine (5.27g, THF 66.6mmol) (10mL) solution.Stirred reaction mixture 3 hours adds H then
2O (30mL).Filtering precipitate with the washing of 1N HCL and ether, obtains the 1-{3-tertiary butyl-1-[3-(amino methyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea (2.28g, 97%), be white solid, need not to be further purified and can be used for next step.MS(ESI)m/z：424(M+H
+)。
Embodiment K
Benzylamine (16.5g, 154mmol) and bromoethyl acetate (51.5g adds K in ethanol 308mmol) (500mL) solution
2CO
3(127.5g, 924mmol).Stirring at room mixture 3 hours filters, and with EtOH washing, vacuum concentration, chromatography produces N-(2-oxyethyl group-2-oxygen ethyl)-N-(phenyl methyl)-glycine ethyl ester (29g, 67%).
1H NMR(CDCl
3)：δ7.39-7.23(m，5H)，4.16(q，J＝7.2Hz，4H)，3.91(s，2H)，3.54(s，4H)，1.26(t，J＝7.2Hz，6H)；MS(ESI)：m/e：280(M++H).
N-(2-oxyethyl group-2-oxygen ethyl)-N-(phenyl methyl)-glycine ethyl ester (7.70g, 27.6mmol) methylamine solution (25-30%, 50mL) a sealed tube internal heating to 50 ℃ 3 hours, be cooled to room temperature, vacuum concentration, produce N-(2-methylamino-2-oxygen ethyl)-N-(phenyl methyl)-glycine methane amide, output (7.63g).
1HNMR(CDCl
3)：δ7.35-7.28(m，5H)，6.75(brs，2H)，3.71(s，2H)，3.20(s，4H)，2.81(d，J＝5.6Hz，6H)；MS(ESI)m/e 250(M+H
+)。
N-(2-methylamino-2-oxygen ethyl)-(3.09g adds 10%Pd/C (0.15g) to N-(phenyl methyl)-glycine methane amide in the mixture of MeOH 11.2mmol) (30mL).Stir this mixture, at 40psi H
2Under be heated to 40 ℃ 10 hours, filter and vacuum concentration, produce N-(2-methylamino-2-oxygen ethyl)-glycine methane amide, output (1.76g).
1H NMR(CDCl
3)：δ6.95(brs，2H)，3.23(s，4H)，2.79(d，J＝6.0，4.8Hz)，2.25(brs 1H)；MS(ESI)m/e 160(M+H
+)。
Embodiment 1
At 1-methyl-[1,2,4] triazolidine-3, the 5-diketone (188mg, 16.4mmol) and sodium hydride (20mg, add in DMSO 0.52mmol) (1mL) solution embodiment E (86mg, 0.2mmol).The stirring at room reaction is spent the night, and uses H
2CH is used in O (10mL) quencher
2C
12Extraction separates organic layer, uses the salt water washing, Na
2SO
4Drying, vacuum concentration.Resistates produces 1-(the 3-tertiary butyl-1-{3-[(1-methyl-3,5-dioxy-1,2,4-triazolidine-4-yl) methyl by preparation HPLC purifying] phenyl }-1H-pyrazoles-5-yl)-(embodiment 1,14mg) for urea for 3-(naphthalene-1-yl).
1HNMR(CD
30D)：δ7.88-7.86(m，2H)，7.71-7.68(m，2H)，7.58(m，2H)，7.60-7.42(m，5H)，6.49(s，1H)，4.85(s，1H)，1.34(s，9H)，1.27(s，6H)；MS(ESI)m/z：525(M+H
+)。
Embodiment 2
According to the mode synthesising title compound that is similar to embodiment 1, use embodiment G, produce 1-(the 3-tertiary butyl-1-{3-[(1-methyl-3,5-dioxy-1,2,4-triazolidine-4-yl) methyl] phenyl }-1H-pyrazoles-5-yl)-3-(4-chloro-phenyl-) urea.
1H NMR(CD
30D)：δ7.2-7.5(m，7H)，6.40(s，1H)，4.70(s，2H)，2.60(d，J＝14Hz，2H)，1.90(m，1H)，1.50(m，1H)，1.45(s，9H)，1.30(m，2H)，1.21(s，3H)，1.18(s，6H)；MS(ESI)m/z：620(M+H
+)。
Embodiment 3
At N
2,-10 ℃, agitate compounds 1,1-dioxy-[1,2,5] thiadiazolidine-3-ketone (94mg, 0.69mmol) and NaH (5.5mg, 0.23mmol) mixed solution in THF (2mL) is 1 hour, up to all NaH dissolving.(100mg, 0.23mmol), the stirring at room reaction is spent the night, and uses H to add embodiment E
2CH is used in the O quencher
2C
12Extraction.The organic layer that vacuum concentration merges, resistates produces 1-(the 3-tertiary butyl-1-{[3-(1 by preparation HPLC purifying, 1,3-three oxygen-[1,2,5] methyl thiadiazolidine-2-yl)] phenyl }-1H-pyrazoles-5-yl)-3-(naphthalene-1-yl) urea (18mg), be white powder.
1H NMR(CD
3OD)：δ7.71-7.44(m，11H)，6.45(s，1H)，4.83(s，2H)，4.00(s，2H)，1.30(s，9H)。MS(ESI)m/z：533.40(M+H
+)。
Embodiment 4
According to the mode that is similar to embodiment 3, use embodiment G to obtain title compound.Generation 1-(the 3-tertiary butyl-1-{[3-(1,1,3-three oxygen-[1,2,5] thiadiazolidine-2-yl) methyl] phenyl }-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea.
1H NMR(CD
3OD)：δ7.38-7.24(m，8H)，6.42(s，1H)，4.83(s，2H)，4.02(s，2H)，1.34(s，9H)；MS(ESI)m/z：517(M+H
+)。
Embodiment 5
At 0 ℃, at chloro sulfonyl isocyanate (19.8 μ L, CH 0.227mmol)
2C
12(18.8 μ L 0.227mmol), add speed control and make the reaction soln temperature be no more than 5 ℃ to add tetramethyleneimine in the stirred solution (0.5mL).Stir after 1.5 hours, add embodiment J (97.3mg, 0.25mmol) and Et3N (95 μ L, CH 0.678mmol)
2C
12Solution (1.5mL), adding speed is no more than 5 ℃ for making temperature of reaction.When interpolation was finished, reacting by heating solution to room temperature and stirring spent the night.Pour reaction mixture into 10%HCL, use CH
2C
12Extraction, the saturated NaC of organic layer
1Washing, MgSO
4Drying, and filter.Except that after desolvating, crude product produces 1-(the 3-tertiary butyl-1-[[3-N-[[(1-pyrrolidyl carbonyl) amino by preparation HPLC purifying] alkylsulfonyl] amino methyl] phenyl]-1H-pyrazoles-5-yl)-3-(4-chloro-phenyl-) urea.
1H NMR(CD
3OD)：δ7.61(s，1H)，7.43-7.47(m，3H)，7.23-7.25(dd，J＝6.8Hz，2H)，7.44(dd，J＝6.8Hz，2H)，6.52(s，1H)，4.05(s，2H)，3.02(m，4H)，1.75(m，4H)，1.34(s，9H)；MS(ESI)m/z：574.00(M+H
+)。
Embodiment 6
According to the mode that is similar to embodiment 5, use example I to prepare title compound, produce 1-(the 3-tertiary butyl-1-[[3-N-[[(1-pyrrolidyl carbonyl) amino] alkylsulfonyl] amino methyl]-phenyl]-1H-pyrazoles-5-yl)-3-(naphthalene-1-yl) urea.
1HNMR(CDCl
3)：δ7.88(m，2H)，7.02-7.39(m，2H)，7.43-7.50(m，7H)，6.48(s，1H)，4.45(s，1H)，3.32-3.36(m，4H)，1.77-1.81(m，4H)，1.34(s，9H)；MS(ESI)m/z：590.03(M+H
+)。
Embodiment 7
At 0 ℃, at chloro sulfonyl isocyanate (19.8 μ L, 0.227mmol) CH
2Cl
2(97.3mg, 0.25mmol), adding speed is no more than 5 ℃ for making the reaction soln temperature to add embodiment J in (0.5 μ L) stirred solution.Stir after 1.5 hours, add tetramethyleneimine (18.8 μ L, 0.227mmol) and Et
3N (95 μ L, CH 0.678mmol)
2C
12(1.5mL) solution, adding speed is no more than 5 ℃ for making temperature of reaction.When interpolation was finished, reacting by heating solution to room temperature and stirring spent the night.Pour reaction mixture into 10%HCL, use CH
2C
12Extraction, the saturated NaC of organic layer
1Extraction, Mg
2SO
4Drying and filtration.Except that after desolvating, crude product produces 1-(the 3-tertiary butyl-1-[[3-N-[[(1-pyrrolidyl alkylsulfonyl) amino by preparation HPLC purifying] carbonyl] amino methyl] phenyl]-1H-pyrazoles-5-yl)-3-(4-chloro-phenyl-) urea.
1HNMR(CDCl
3)：δ7.38(m，1H)，7.36-7.42(m，3H)，7.23(d，J＝8.8Hz，2H)，7.40(d，J＝8.8Hz，2H)，6.43(s，1H)，4.59(s，1H)，4.43(s，2H)，1.81(s，2H)，1.33(s，9H)：MS(ESI)m/z：574.10(M+H
+)。
Embodiment 8
According to the mode that is similar to embodiment 7, use example I to prepare title compound, produce 1-(the 3-tertiary butyl-1-[[3-N-[[(1-pyrrolidyl alkylsulfonyl) amino] carbonyl] amino methyl]-phenyl]-1H-pyrazoles-5-yl)-3-(naphthalene-1-yl) urea.
1HNMR(CDCl
3)：δ7.88(m，2H)，7.02-7.39(m，2H)，7.43-7.50(m，7H)，6.48(s，1H)，4.45(s，1H)，3.32-3.36(m，4H)，1.77-1.81(m，4H)，1.34(s，9H)；MS(ESI)m/z：590.03(M+H
+)。
Embodiment 9
Reagent BB (36mg, 0.15mmol), example I (62mg, 0.15mmol), HOBt (40mg, 0.4mmol) and NMM (0.1mL, add in DMF 0.9mmol) (10mL) solution EDCI (58mg, 0.3mmol).After stirring is spent the night, pour mixture into water (15mL), with EtOAc (35mL) extraction.Merge organic layer, use the salt water washing, use Na
2SO
4Drying, vacuum concentration.Resistates produces 1,5,7-trimethylammonium-2,4-dioxy-3-azabicyclic [3.3.1] nonane-7-carboxylic acid 3-[3-tertiary butyl-5-(3-naphthalene-1-base-urea groups)-pyrazol-1-yl by preparation TLC purifying] benzyl acid amides (22mg).
1H NMR(CDCl
3)：δ8.40(s，1H)，8.14(d，J＝8.0Hz，2H)，7.91(s，1H)，7.87(s，1H)，7.86(d，J＝7.2Hz，1H)，7.78(d，J＝7.6Hz，1H)，7.73(d，J＝8.4Hz，1H)，7.69(d，J＝8.4Hz，1H)，7.57-7.40(m，4H)，7.34(d，J＝7.6Hz，1H)，6.69(s，1H)，6.32(t，J＝5.6Hz，1H)，5.92(brs，1H)，4.31(d，J＝5.6Hz，2H)，2.37(d，J＝14.8Hz，2H)，1.80(d，J＝13.2Hz，1H)，1.35(s，9H)，1.21(d，J＝13.2Hz，1H)，1.15(s，3H)，1.12(d，J＝12.8Hz，2H)，1.04(s，6H)；MS(ESI)m/z：635(M+H
+)。
Embodiment 10
According to the mode that is similar to embodiment 9, use embodiment J synthesising title compound, produce 1,5,7-trimethylammonium-2,4-dioxy-3-azabicyclic [3.3.1] nonane-7-carboxylic acid 3-{3-tertiary butyl-5-[3-(4-chloro-phenyl)-urea groups]-pyrazol-1-yl } the benzyl acid amides.
1H NMR(CDCl
3)：δ8.48(s，1H)，7.78(s，1H)，7.75(d，J＝8.0Hz，1H)，7.69(s，1H)，7.53(t，J＝8.0Hz，1H)，7.48(d，J＝8.8Hz，2H)，7.26(m，3H)，6.62(s，1H)，6.35(t，J＝6.0Hz，1H)，5.69(brs，1H)，4.26(d，J＝6.0Hz，2H)，2.48(d，J＝14.0Hz，2H)，1.87(d，J＝13.6Hz，1H)，1.35(s，9H)，1.25(m，6H)，1.15(s，6H)；MS(ESI)m/z：619(M+H
+)。
Embodiment 11
Under the room temperature, and example I (41mg, 0.1mmol), the Kemp acid anhydrides (24mg, 0.1mmol) and Et
3(100mg, mixture 1mmol) is at anhydrous CH for N
2C
12Stir (2mL) and spend the night vacuum concentration.(20mL) joins resistates with dry-out benzene, mixture refluxed 3 hours, vacuum concentration, and by preparation HPLC purifying, produce the 3-{3-[3-tertiary butyl-5-(3-naphthalene-1-base-urea groups)-pyrazol-1-yl]-benzyl }-1,5-two-methyl-2,4-dioxy-3-aza-bicyclo [3.3.1] nonane-7-carboxylic acid (8.8mg, 14%).
1H NMR(CD
3OD)：δ7.3-7.4(m，2H)，7.20(m，2H)，7.4-7.6(m，7H)，6.50(m，1H)，4.80(s，2H)，2.60(d，J＝14Hz，2H)，1.90(m，1H)，1.40(m，1H)，1.30(m，2H)，1.20(s，3H)，1.15(s，6H)；MS(ESI)m/z：636(M+H
+)。
Embodiment 12
According to the mode that is similar to embodiment 11, use embodiment J synthesising title compound, produce the 3-{3-[3-tertiary butyl-5-(3-naphthalene-1-base-urea groups)-pyrazol-1-yl]-benzyl }-1,5-dimethyl-2,4-dioxy-3-azabicyclic [3.3.1] nonane-7-carboxylic acid.
1H NMR(CD
3OD)：δ7.2-7.5(m，7H)，6.40(s，1H)，4.70(s，2H)，2.60(d，J＝14Hz，2H)，1.90(m，1H)，1.50(m，1H)，1.45(s，9H)，1.30(m，2H)，1.21(s，3H)，1.18(s，6H)；MS(ESI)m/z：620(M+H
+)。
Embodiment 13
According to the mode that is similar to embodiment 1, use embodiment E and 4,4-dimethyl-3,5-dioxy-pyrazolidine, synthesising title compound produces 1-(the 3-tertiary butyl-1-{3-[(4,4-dimethyl-3,5-dioxy pyrazolidine-1-yl) methyl] phenyl }-1H-pyrazoles-5-yl)-3-(naphthalene-1-yl) urea.
1HNMR(CD
3OD)：δ7.88-7.86(m，2H)，7.71-7.68(m，2H)，7.58(m，2H)，7.60-7.42(m，5H)，6.49(s，1H)，4.85(s，1H)，1.34(s，9H)，1.27(s，6H)；MS(ESI)m/z：525(M+H
+)。
Embodiment 14
According to the mode that is similar to embodiment 1, use embodiment G and 4,4-dimethyl-3,5-dioxy-pyrazolidine synthesising title compound, produce 1-(the 3-tertiary butyl-1-{3-[(4,4-dimethyl-3,5-dioxy pyrazolidine-1-yl) methyl] phenyl }-1H-pyrazoles-5-yl)-3-(4-chloro-phenyl-) urea.
1H NMR(CD
3OD)：δ7.60-7.20(m，8H)，6.43(s，1H)，4.70(s，1H)，1.34(s，9H)，1.26(s，6H)；MS(ESI)m/z：509，511(M+H
+)。
Embodiment 15
Embodiment B is with 2N LiOH saponification in MeOH, at the acid that produces (64.2mg, 0.15mmol) the middle HOBt (30mg that adds, 0.225mmol), (24mg is 0.15mmol) with 4-methylmorpholine (60mg for embodiment K, 0.60mmol 4.0 equivalents), and DMF (3mL) and EDCI (43mg, 0.225mmol).The stirring at room reaction mixture spends the night, and pours H into
2Among the O (3mL), collect white precipitate, HPLC is further purified by preparation, generation 1-[1-(3-{ two [(methylamino formyl radical) methyl] formamyl } phenyl)-the 3-tertiary butyl-1H-pyrazoles-5-yl]-3-(naphthalene-1-yl) urea (40mg).
1H NMR(CDCl
3)：δ8.45(brs，1H)，8.10(d，J＝7.6Hz，1H)，7.86-7.80(m，2H)，7.63-7.56(m，2H)，7.52(s，1H)，7.47-7.38(m，3H)，7.36-7.34(m，1H)，7.26(s，1H)，7.19-7.17(m，2H)，6.60(s，1H)，3.98(s，2H)，3.81(s，3H)，2.87(s，3H)，2.63(s，3H)，1.34(s，9H)；MS(ESI)m/z：570(M+H
+)。
Embodiment 16
According to the mode that is similar to embodiment 15; use Embodiment C (37mg) and embodiment K synthesising title compound, generation 1-[1-(3-{ two [(methylamino formyl radical) methyl] formamyl } phenyl)-the 3-tertiary butyl-1H-pyrazoles-5-yl]-3-(4-chloro-phenyl-) urea.
1H NMR(CD
3OD)：δ8.58(brs，1H)，8.39(brs，1H)，7.64-7.62(m，3H)，7.53-7.51(m，1H)，7.38(d，J＝9.2Hz，2H)，7.25(d，J＝8.8Hz，2H)，6.44(s，1H)，4.17(s，2H)，4.11(s，2H)，2.79(s，3H)，2.69(s，3H)，1.34-1.28(m，12H)；MS(ESI)m/z：554(M+H
+)。
Embodiment 17
Embodiment B is with 2N LiOH saponification in MeOH, under the vigorous stirring, the acid that produces (0.642g, add in anhydrous THF (25mL) solution 1.5mmol) fresh distillatory triethylamine (0.202g, 2.0mmol) and pivalyl chloride (0.216g, 1.80mmol).-78 ℃ were stirred 15 minutes, 0 ℃ was stirred after 45 minutes, cooling mixture is to-78 ℃ again, transfer to then in the THF solution of lithium salts of D-4-phenyl-oxazolidines-2-ketone [the lithium salts reagent of *: oxazolidone can be in advance by at-78 ℃, in the THF solution of D-4-phenyl-azoles alkane-2-ketone, slowly just adding-BuLi (2.50M hexane solution, 1.20mL, 3.0mmol) preparation].-78 ℃ of stirring reaction solution 2 hours, stirred overnight at room temperature is used the aqueous ammonium chloride quencher then, with methylene dichloride (100mL) extraction.Organic layer drying (the Na that merges
2SO
4) and vacuum concentration.Resistates produces the D-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl by preparation HPLC purifying]-the 2H-pyrazole-3-yl }-3-(naphthalene-1-yl) urea (207mg, 24%).
1H NMR(CDCl
3)：δ8.14-8.09(m，2H)，8.06(s，1H)，7.86-7.81(m，4H)，7.79(s，1H)，7.68-7.61(m，2H)，7.51-7.40(m，9H)，6.75(s，1H)，5.80(t，J＝9.2，7.6Hz，1H)，4.89(t，J＝9.2Hz，1H)，4.42(dd，J＝9.2，7.6Hz，1H)，1.37(s，9H)，MS(ESI)m/z：574(M+H
+)。
Embodiment 18
According to the mode that is similar to embodiment 17, use the synthetic title mixture of Embodiment B and L-4-phenyl-oxazolidines-2-ketone, produce the L-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-3-(naphthalene-1-yl) urea.
1H NMR(CDC
13)：δ8.14-8.09(m，2H)，8.06(s，1H)，7.86-7.81(m，4H)，7.79(s，1H)，7.68-7.61(m，2H)，7.51-7.40(m，9H)，6.75(s，1H)，5.80(t，J＝9.2，7.6Hz，1H)，4.89(t，J＝9.2Hz，1H)，4.42(dd，J＝9.2，7.6Hz，1H)，1.37(s，9H)；MS(ESI)m/z：574(M+H
+)。
Embodiment 19
According to the mode that is similar to embodiment 17, use Embodiment C and D-4-phenyl-oxazolidines-2-ketone synthesising title compound, produce the D-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-3-(4-chloro-phenyl-) urea.
1H NMR(CDCl
3)：δ7.91(s，1H)，7.85(d，J＝8.0Hz，1H)，7.79(d，J＝7.6Hz，1H)，7.71(m，1H)，7.65(m，1H)，7.49-7.40(m，8H)，7.26-7.24(m，2H)，6.68(s，1H)，5.77(dd，J＝8.8，8.0Hz，1H)，4.96(t，8.8Hz，1H)，4.44(dd，J＝8.8，8.0Hz，1H)，1.36(s，9H)；MS(ESI)m/z：558(M+H
+)。
Embodiment 20
According to the mode that is similar to embodiment 17, use Embodiment C and L-4-phenyl-oxazolidines-2-ketone synthesising title compound, produce the L-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-3-(4-chloro-phenyl-) urea.
1H NMR(CDCl
3)：δ7.91(s，1H)，7.85(d，J＝8.0Hz，1H)，7.79(d，J＝7.6Hz，1H)，7.71(m，1H)，7.65(m，1H)，7.49-7.40(m，8H)，7.26-7.24(m，2H)，6.68(s，1H)，5.77(dd，J＝8.8，8.0Hz，1H)，4.96(t，8.8Hz，1H)，4.44(dd，J＝8.8，8.0Hz，1H)，1.36(s，9H)；MS(ESI)m/z：558(M+H
+)。
Embodiment L
At N
2Down, 0 ℃, at the CH of (3-nitro-phenyl)-acetate (2g)
2C
12Drip oxalyl chloride (1.1ml) in (40ml has the DMF of catalytic amount) stirred suspension.Stirred reaction mixture 40 minutes adds morpholine (2.5g).Stir after 20 minutes filter reaction mixture.Vacuum concentrated filtrate produces 1-morpholine-4-base-2-(3-nitro-phenyl)-ethyl ketone, is solid (2g).The hydrogenation 3 hours under 30psi of the mixture of 10%Pd (0.2g) in ethanol (30ml) is filtered on diatomite on 1-morpholine-4-base-2-(3-nitro-phenyl)-ethyl ketone (2g) and the gac.Vacuum is removed volatile matter, and 2-(3-amino-phenyl)-1-morpholine-4-base-ethyl ketone (1.7g) is provided.(1.7g, solution 7.7mmol) are dissolved among the 6N HCL (15ml) 2-2-(3-amino-phenyl)-1-morpholine-4-base-ethyl ketone, are cooled to 0 ℃ and vigorous stirring.Water (8ml) solution that adds Sodium Nitrite (0.54g).30 minutes, 6N HCl (30ml) solution of adding tin chloride (II) dihydrate (10g).0 ℃ of stirred reaction mixture 3 hours.Regulate pH to 14 with solid potassium hydroxide, extract with EtOAc.The organic extract that vacuum concentration merges provides 2-(3-hydrazine-phenyl)-1-morpholine-4-base-ethyl ketone (1.5g).2-(3-diazanyl phenyl)-1-morpholine-4-base-ethyl ketone (3g) and 4, (1.9g, 15mmol) solution at ethanol (60ml) and 6N HCL (1ml) refluxed 1 hour 4-dimethyl-3-oxygen valeronitrile, was cooled to room temperature.Add sodium bicarbonate neutralization reaction mixture.Filter slurry, vacuum is removed volatile matter, and resistates is provided, the resistates ethyl acetate extraction.The vacuum hydro-extraction volatile matter provides 2-[3-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) phenyl]-1-morpholinyl ethyl ketone (4g), this product just need not be further purified and can use.
Embodiment 21
At N
2Down, 0 ℃, (0.2g, 0.58mmol) (0.10g is 0.6mmol) at anhydrous CH with 1-naphthyl isocyanic ester to be stirred in embodiment L
2C
12Mixture (4ml) 18 hours.Solvent removed in vacuo, crude product are used ethyl acetate/hexane/CH by column chromatography purification
2C
12(3/1/0.7), produce the 1-{3-tertiary butyl-1-[3-(2-morpholinyl-2-oxygen ethyl) phenyl as elutriant (0.11g, pale solid)]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea.mp：194-196；
1H NMR(200MHz，DMSO-d
6)：δ9.07(1H，s)，8.45(s，1H)，8.06-7.93(m，3H)，7.69-7.44(m，7H)，7.33-7.29(d，6.9Hz，1H)，6.44(s，1H)，3.85(m，2H)，3.54-3.45(m，8H)，1.31(s，9H)；MS：
Embodiment 22
According to the mode that is similar to embodiment 21, use embodiment L (0.2g, 0.58mmol) and 4-chloro-phenyl-isocyanic ester (0.09g, 0.6mmol) synthesising title compound produce the 1-{3-tertiary butyl-1-[3-(2-morpholinyl-2-oxygen ethyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea.mp：100 104；
1H NMR(200MHz，DMSO-d
6)：δ9.16(s，1H)，8.45(s，1H)；7.52-7.30(m，8H)，6.38(s，1H)，3.83(m，1H)，3.53-3.46(m，8H)，1.30(s，9H)；MS：
Embodiment 23
According to the mode that is similar to embodiment 21, use embodiment L (0.2g, 0.58mmol) and phenyl isocyanate (0.09g, 0.6mmol) synthesising title compound produce the 1-{3-tertiary butyl-1-[3-(2-morpholinyl-2-oxygen ethyl) phenyl]-1H-pyrazoles-5-yl }-the 3-phenylurea.
Embodiment 24
According to the mode that is similar to embodiment 21, use embodiment L (0.2g, 0.58mmol) and 1-isocyanic acid-4-methoxyl group-naphthalene synthesising title compound, produce the 1-{3-tertiary butyl-1-[3-(2-morpholinyl-2-oxygen ethyl) phenyl]-1H-pyrazoles-5-yl }-3-(1-methoxynaphthalene-4-yl) urea.
Embodiment M
According to the mode that is similar to Embodiment C, use embodiment A and phenylcarbimide synthesising title compound, produce 3-(the 3-tertiary butyl-5-(3-phenyl urea groups)-1H-pyrazol-1-yl) benzoic ether.
Embodiment N
(3-nitrophenyl) acetate (23g, the vacuum concentration H of (250ml) solution of methyl alcohol 127mmol) and catalytic amount
2SO
4Reflux 18 hours.The vacuum concentration reaction mixture is a yellow oil.This oil is dissolved in the methyl alcohol (250ml), in ice bath, stirs 18 hours fugitive constituents, in this solution, slowly feed ammonia flow simultaneously.Vacuum is removed volatile matter.Use the diethyl ether debris, dry 2-(3-nitrophenyl) ethanamide (14g, pale solid) that obtains.
1HNMR(CDCl
3)：δ8.1(s，1H)，8.0(d，1H)，7.7(d，1H)，7.5(m，1H)，7.1(bds，1H)，6.2(brs，1H)，3.6(s，2H)。
10%Pd (1g) hydrogenation 18 hours in ethanol (100ml), under the 30psi is filtered on diatomite on raw material that reacts previously (8g) and the gac.Vacuum is removed volatile matter, and 2-(3-aminophenyl) ethanamide (5.7g) is provided.(7g 46.7mmol) is dissolved among the 6N HCL (100ml), is cooled to 0 ℃ and vigorous stirring with the solution of this material.Add Sodium Nitrite (3.22g, water 46.7mmol) (50ml) solution.After 30 minutes, add the solution of tin chloride (II) dihydrate (26g) in 6N HCL (100ml).0 ℃ of stirred reaction mixture 3 hours.Regulate pH to 14 with the 50%NaOH aqueous solution, use ethyl acetate extraction.The organic extract that vacuum concentration merges provides 2-(3-diazanyl phenyl) ethanamide.
The raw material that reacts previously (about 15mmol) and 4, (1.85g's 4-dimethyl-3-oxygen valeronitrile 15mmol) refluxed 1 hour in ethanol (60ml) and 6N HCL (1.5ml), was cooled to room temperature.Add solid sodium bicarbonate neutralization reaction mixture.Filter slurry, vacuum is removed volatile matter, and resistates is provided, this resistates ethyl acetate extraction.Solvent removed in vacuo provides 2-[3-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) phenyl] ethanamide, be white solid (3.2g) that this product just need not be further purified and can use.
Embodiment 25
At N
2Down, room temperature, (2g, 0.73mmol) (0.124g is 0.73mmol) at anhydrous CH with 1-naphthyl isocyanic ester to stir embodiment N
2C
12Mixture (4ml) 18 hours.Solvent removed in vacuo, crude product washs with ethyl acetate (8ml), vacuum-drying produces the 1-{3-tertiary butyl-1-[3-(carbamyl ylmethyl) phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea, be white solid (0.22g).Mp:230 (decomposition);
1H NMR (200MHz, DMSO-d
6): δ 9.12 (s, 1H), 8.92 (s, 1H), 8.32-8.08 (m, 3H), 7.94-7.44 (m, 8H), 6.44 (s, 1H), 3.51 (s, 2H), 1.31 (s, 9H); MS:
Embodiment 26
According to the mode that is similar to embodiment 23; use embodiment N (0.2g; 0.73mmol) and 4-chloro-phenyl-isocyanic ester (0.112g; 0.73mmol) synthesising title compound; produce the 1-{3-tertiary butyl-1-[3-(carbamyl ylmethyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea, be white solid (0.28g).Mp:222224 (decomposition).
1H NMR(200MHz，DMSO-d
6)；δ9.15(s，1H)，8.46(s，1H)，7.55-7.31(m，8H)，6.39(s，1H)，3.48(s，2H)，1.30(s，9H)；MS：
Embodiment O
According to the mode that is similar to Embodiment C, use embodiment A and 1-isocyanic acid-4-methoxyl group-naphthalene, synthesising title compound produces 3-(the 3-tertiary butyl-5-(3-(1-methoxynaphthalene-4-yl) urea groups)-1H-pyrazol-1-yl) benzoic ether.
Embodiment 27
According to the mode that is similar to embodiment 17, use embodiment M and D-4-phenyl-oxazolidines-2-ketone synthesising title compound, produce the D-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-the 3-phenylurea.
Embodiment 28
According to the mode that is similar to embodiment 17, use embodiment M and L-4-phenyl-oxazolidines-2-ketone synthesising title compound, produce the L-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-the 3-phenylurea.
Embodiment P
The hydrogenation 18 hours under 30psi of the mixture of 10%Pd (1g) in ethanol (50ml) is filtered on the diatomite on 3-(3-amino-phenyl)-methyl acrylate (6g) and the gac.Vacuum is removed volatile matter, and 3-(3-amino-phenyl) methyl propionate (6g) is provided.
(5.7g 31.8mmol) is dissolved in the solution of 6N HCL (35ml) to vigorous stirring front reaction raw materials, is cooled to 0 ℃, adds water (20ml) solution of Sodium Nitrite (2.2g).After 1h hour, add the solution of tin chloride dihydrate (18g) in 6N HCL (35ml).0 ℃ was stirred this mixture 3 hours.Regulate pH to 14 with solid KOH, extract with EtOAc.The organic extract that vacuum concentration merges provides 3-(3-diazanyl-phenyl) methyl propionate (1.7g).
(1.7g, 8.8mmol) with 4, (1.2g, 9.7mmol) stirred solution in ethanol (30ml) and 6N HCL (2ml) refluxed 18 hours 4-dimethyl-3-oxygen valeronitrile the raw material that reacts previously, was cooled to room temperature.Vacuum is removed volatile matter, and resistates is dissolved among the EtOAc, with 1N NaOH solution washing.Organic layer drying (Na
2SO
4) and vacuum concentration, resistates is by column chromatography purification, and the hexane that uses 30% ethyl acetate provides 3-[3-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) phenyl as elutriant] methyl propionate (3.2g), this product just need not be further purified and can use.
Embodiment 29
At N
2Down, room temperature, (0.35g, 1.1mmol) (0.19g is 1.05mmol) at anhydrous CH with 1-naphthyl isocyanic ester to stir embodiment P
2C
12Mixture (5ml) 20 hours.Solvent removed in vacuo, the resistates of stirring at room in the THF that contains lithium hydroxide (0.1g) (3ml)/MeOH (2ml)/water (1.5ml) solution 3 hours is subsequently with EtOAc and the dilution of rare citric acid solution.Organic layer drying (Na
2SO
4), vacuum is removed volatile matter.Resistates uses the CH of 3% methyl alcohol by column chromatography purification
2C
12As elutriant, generation 3-(the 3-{3-tertiary butyl-5-[3-(naphthalene-1-yl) urea groups]-the 1H-pyrazol-1-yl } phenylpropionic acid (0.22g is with brown brown solid), mp:105-107;
1H NMR (200MHz, CDC
13): δ 7.87-7.36 (m, 10H), 7.18-7.16 (m, 1H), 6.52 (s, 1H), 2.93 (t, J=6.9Hz, 2H), 2.65 (t, J=7.1Hz, 2H), 1.37 (s, 9H); MS
Embodiment 30
According to the mode that is similar to embodiment 29, use embodiment P (0.30g, 0.95mmol) and 4-chloro-phenyl-isocyanic ester (0.146g, 0.95mmol) synthesising title compound, generation 3-(the 3-{3-tertiary butyl-5-[3-(4-chloro-phenyl-) urea groups]-the 1H-pyrazol-1-yl } phenyl) propionic acid (0.05g, white solid).mp：8587；
1H NMR(200MHz，CDCl
3)：δ8.21(s，1H)，7.44-7.14(m，7H)，6.98(s，1H)，6.55(s，1H)，2.98(t，J＝5.2Hz，2H)，2.66(t，J＝5.6Hz，2H)，1.40(s，9H)；MS
Embodiment Q
10%Pd (0.3g), filters on the diatomite 30psi hydrogenation 18 hours at the mixture of ethanol (20ml) on 3-(4-aminophenyl) ethyl propenoate (1.5g) and the gac.Vacuum is removed volatile matter, and 3-(4-aminophenyl) ethyl propionate (1.5g) is provided.
(1.5g 8.4.mmol) is dissolved among the 6N HCL (9ml) solution of front reaction raw materials, is cooled to 0 ℃ and vigorous stirring.Water (7ml) solution that adds Sodium Nitrite (0.58g).After 1 hour, be added in tin chloride (II) dihydrate (5g) of 6N HCL (10ml).0 ℃ of stirred reaction mixture 3 hours.Regulate pH to 14 with solid KOH, extract with EtOAc.The organic extract that vacuum concentration merges provides 3-(4-diazanyl-phenyl)-ethyl propionate (1g).
(1g, 8.8mmol) with 4,4-methyl-3-oxygen valeronitrile (0.7g) refluxed 18 hours in ethanol (8ml) and 6N HCL (1ml) raw material that reacts previously, was cooled to room temperature.Vacuum is removed volatile matter.Resistates is dissolved in the ethyl acetate, washs with the 1N aqueous sodium hydroxide washes.Organic layer drying (Na
2SO
4) and vacuum concentration.Resistates uses at CH by column chromatography purification
2C
120.7% methyl alcohol as elutriant, the 3-{4-[3-tertiary butyl-5-(3-(naphthalene-1-yl) urea groups)-1H-pyrazol-1-yl is provided] phenyl ethyl propionate (0.57g).
Embodiment 31
At N
2Down, room temperature, (0.25g, 0.8mmol) (0.13g is 0.8mmol) at anhydrous CH with 1-naphthyl isocyanic ester to stir embodiment Q
2C
12Mixture (5ml) 20 hours.Solvent removed in vacuo, the resistates of stirring at room in the THF that contains lithium hydroxide (0.1g) (3ml)/MeOH (2ml)/water (1.5ml) solution 3 hours is with EtOAc and the dilution of rare citric acid solution.Organic layer drying (Na
2SO
4) and vacuum remove volatile matter, resistates uses the CH of 4% methyl alcohol by column chromatography purification
2C
12Solution produces the 3-{4-[3-tertiary butyl-5-(3-(naphthalene-1-yl) urea groups)-1H-pyrazol-1-yl as elutriant] phenyl } propionic acid (0.18g, pale solid).mp：120122；
1H NMR(200MHz，CDCl
3)：δ7.89-7.06(m，11H)，6.5(s，1H)，2.89(m，2H)，2.61(m，2H)，1.37(s，9H)；MS
Embodiment 32
According to the mode that is similar to embodiment 31, use embodiment Q (0.16g, 0.5mmol) and 4-chloro-phenyl-isocyanic ester (0.077g, 0.5mmol) synthesising title compound, produce the 3-{4-[3-tertiary butyl-5-(3-(4-chloro-phenyl-) urea groups)-1H-pyrazol-1-yl] phenyl } propionic acid (0.16g, pale solid).mp：112-114。
1HNMR(200MHz，CDCl
3)：δ8.16(s，1H)，7.56(s，1H)，7.21(s，2H)，7.09(s，2H)，6.42(s，1H)，2.80(m，2H)，2.56(m，2H)，1.32(s，9H)；MS
Embodiment R
250mL pressurized vessel (ACE glass tetrafluoroethylene nut) pack into be dissolved in THF (～100mL) 3-nitrobiphenyl (and 20g, 0.10mol) and 10%Pd/C (3g).Feed H in this reactor
2(g) and purge three times.Feed 40psi H
2(g) react, and place Parr vibration hydrogenation equipment, spend the night in the room temperature vibration.HPLC shows that reaction is finished, and therefore, reaction mixture filters by the diatomite bed, and evaporation produces amine: 16.7g (98% productive rate).
In a 250mL erlenmeyer flask of being furnished with magnetic stirring bar, with react previously (4.40g 0.026mol) joins 6N HCL (40mL), is cooled to 0 ℃ with ice bath soon.Drip NaNO
2Water (5mL) solution of (2.11g, 0.0306mol, 1.18 equivalents).After 30 minutes, add SnC
12-2H
206N HCl (100mL) solution of (52.0g, 0.23mol, 8.86 equivalents), stirred reaction mixture 3 hours then, is transferred to the round-bottomed flask of a 500mL.In this solution, add 4, (3.25g, 0.026mol) and EtOH (100ml), mixture refluxed 4 hours 4-dimethyl-3-oxygen valeronitrile, vacuum concentration, usefulness EtOAc (2 * 100mL) extracted residues.Resistates uses hexane/EtOAc/Et by column chromatography purification
3N (8: 2: 0.2) produces 0.53g embodiment R.
1H NMR(CDCl
3)：δ7.5(m，18H)，5.8(s，1H)，1.3(s，9H)。
Embodiment 33
In a dry bottle that magnetic stirring bar arranged, with embodiment R (0.145g; 0.50mmol) be dissolved in 2mLCH
2C
12In (anhydrous), add phenyl isocyanate (0.0544mL subsequently; 0.50mmol; 1 equivalent).Reaction remains under the argon gas and stirred 17 hours.Evaporating solvent obtains crystallization, grinds with hexane/EtOAc (4: 1), filters, and produces 1-(the 3-tertiary butyl-1-(3-phenyl)-1H-pyrazoles-5-yl)-3-phenylurea (0.185g, 90%).HPLC purity: 96%; Mp:8084;
1HNMR (CDC
13): δ 7.3 (m, 16H), 6.3 (s, 1H), 1.4 (s, 9H).
Embodiment 34
According to the mode that is similar to embodiment 33, use embodiment R (0.145g; 0.50mmol) and right-chloro-phenyl-isocyanic ester (0.0768g, 0.50mmol, 1 equivalent) synthesising title compound, produce 1-(the 3-tertiary butyl-1-(3-phenyl)-1H-pyrazoles-5-yl)-3-(4-chloro-phenyl-) urea (0.205g, 92%).HPLC purity: 96.5%; Mp:134136.
1H NMR(CDC
13)：δ7.5(m，14H)，7.0(s，1H)，6.6(s，1H)，6.4(s，1H)，1.4(s.9H)。
Embodiment S
According to the mode that is similar to Embodiment C, use embodiment A and 4-fluorophenyl isocyanic ester synthesising title compound, produce 3-(the 3-tertiary butyl-5-(3-(4-fluorophenyl) urea groups)-1H-pyrazol-1-yl) ethyl benzoate.
Embodiment 35
According to the mode that is similar to embodiment 17, use embodiment M and D-4-phenyl-oxazolidines-2-ketone synthesising title compound, produce the D-1-{5-tertiary butyl-2-[3-(2-oxygen-4-phenyl-oxazolidinyl-3-carbonyl) phenyl]-the 2H-pyrazole-3-yl }-3-(naphthalene-1-yl) urea.
Embodiment 36
According to the mode that is similar to embodiment 29, use embodiment P (0.30g, 0.95mmol) and 4-fluorophenyl isocyanic ester (0.146g, 0.95mmol) synthesising title compound, generation 3-(3-(the 3-tertiary butyl-5-(3-(4-fluorophenyl) urea groups)-1H-pyrazol-1-yl) phenyl) propionic acid.
Embodiment T
Embodiment N (2g adds borine-methyl sulphur (18mmol) in THF 7.35mmol) (6ml) stirred solution. mixture heating up refluxed 90 minutes, was cooled to room temperature, afterwards, added 6N HCL, and reflux 10 minutes.Mixture alkalizes with NaOH, extracts with EtOAc.Organic layer drying (Na
2SO
4), filter and vacuum concentration, produce the 3-tertiary butyl-1-[3-(2-amino-ethyl) phenyl]-1H-pyrazoles-5 amine (0.9g).
At N
2Down, room temperature, stir the front reaction raw materials (0.8g, 3.1mmol) and the dimethyl dicarbonate butyl ester (0.7g, 3.5mmol) and catalytic amount DMAP at anhydrous CH
2C
12Mixture (5ml) 18 hours.Vacuum concentration reaction mixture, resistates use CH by column chromatography purification
2C
12In 1% methyl alcohol as elutriant, produce 3-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) the phenylcarbamic acid tert-butyl ester (0.5g).
Embodiment 37
At N
2Down, room temperature, (0.26g, 0.73mmol) (0.123g is 0.73mmol) at anhydrous CH with 1-naphthyl isocyanic ester to stir embodiment T
2C
12Mixture (5ml) 48 hours.Solvent removed in vacuo, resistates are used CH by column chromatography purification
2C
12In 1% methyl alcohol as elutriant (0.15g, pale solid).This solid uses TFA (0.2ml) to handle then 5 minutes, dilutes with EtOAc.Use saturated NaHCO
3Solution and salt water washing organic layer, dry (Na
2SO
4), filter and vacuum concentration, produce the 1-{3-tertiary butyl-1-[3-(2-amino-ethyl) phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea, be solid (80mg) .mp:110-112.
1H NMR(200MHz，DMSO-d
6)：δ9.09(s，1H)，8.90(s，1H)，8.01-7.34(m，11H)，6.43(s，1H)，3.11(m，2H)，2.96(m，2H)，1.29(s，9H)；MS
Embodiment 38
According to the mode that is similar to embodiment 37, use embodiment T (0.15g, 0.42mmol) and 4-chloro-phenyl-isocyanic ester (0.065g, 0.42mmol) synthesising title compound, produce the 1-{3-tertiary butyl-1-[3-(2-amino-ethyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea, be pale solid (20mg).mp：125-127；
1HNMR(200MHz，CDCl
3)：δ8.81(s，1H)，8.66(s，1H)，7.36-7.13(m，8H)，6.54(s，1H)，3.15(brs，2H)，2.97(brs，2H)，1.32(s，9H)；MS
Embodiment U
In the 250mL erlenmeyer flask of magnetic stirring bar is arranged, will between-(9.84g 0.052mol) joins among the 6N HCL (80mL) methyl oxyaniline, is cooled to ℃ with ice bath.Drip NaNO
2Water (10mL) solution of (4.22g, 0.0612mol, 1.18 equivalents).After 30 minutes, SnC
122H
20(104.0g, 0.46mol, 8.86 equivalents) solution in 6N HCl (200mL), stirred reaction mixture 3 hours.Transfer to a 1000mL round-bottomed flask then.In this flask, add 4, and 4-dimethyl-3-oxygen valeronitrile (8.00g, 0.064mol) and EtOH (200mL), mixture backflow 4 hours, vacuum concentration, resistates is from CH
2C
12Recrystallization produces the 3-tertiary butyl-1-(3-p-methoxy-phenyl)-1H-pyrazoles-5-amine, is hydrochloride (13.9g).
(4.65g 0.165mol) is dissolved in 30mL CH to the raw material that reacts previously
2C
12With Et
3Among the N (2.30mL, 0.0165mol, 1 equivalent), stirred 30 minutes.Na is used in the water extraction later on
2SO
4Dry organic phase, vacuum concentration produces brown slurry, free alkali, the 3-tertiary butyl-1-(3-p-methoxy-phenyl)-1H-pyrazoles-5-amine (3.82g, 94.5%) just need not to be further purified and can use.
Embodiment 39
In a dry bottle that magnetic stirring bar arranged, (2.62g 0.0107mol) is dissolved in CH with embodiment U
2C
12In (5mL, anhydrous), add 1-naphthyl isocyanic ester (1.53mL, 0.0107mol, 1 equivalent) subsequently.Reaction remains under the argon gas and stirred 18 hours.Evaporating solvent, EtOAc/ hexane/Et3N (7: 2: 0.5) carries out column chromatography for elutriant subsequently, produces the 1-[3-tertiary butyl-1-(3-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-3-(naphthalene-1-yl) urea (3.4g, 77%) .HPLC:97%; Mp:78-80;
1H NMR (CDCl
3): δ 7.9-6.8 (m, 15H), 6.4 (s, 1H), 3.7 (s, 3H), 1.4 (s, 9H).
Embodiment 40
According to the mode that is similar to embodiment 39, use embodiment U (3.82g; 0.0156mol) and right-chloro-phenyl-isocyanic ester (2.39g, 0.0156mol, 1 equivalent), synthesising title compound, by grinding purifying with hexane/EtOAc (4: 1), filter and produce the 1-[3-tertiary butyl-1-(3-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-3-(4-chloro-phenyl-) urea (6.1g, 98%).HPLC purity: 95%; Mp:158-160;
1H NMR (CDCl
3): δ 7.7 (s, 1H); 87.26.8 (m, 8H), 6.4 (s, 1H), 3.7 (s, 3H), 1.3 (s, 9H).
Embodiment 41
In being furnished with the 100ml round-bottomed flask of magnetic stirring bar, embodiment 39 (2.07g) is dissolved in CH
2C
12(20mL), ice bath is cooled to 0 ℃.Slowly add BBR
3(1M is at CH
2C
12In; 7.5mL).The reacting by heating mixture is to ambient temperature overnight.
Add BBR again
3(1M is at CH
2C
12In, 2 * 1mL, 9.5mmol, total addition level), adding the MeOH quencher should reaction.Evaporating solvent produces crystallisate, uses CH
2C
12/ MeOH (9.6: 0.4) is an elutriant, goes up chromatography at silica gel (30g), produces the 1-[3-tertiary butyl-1-(3-hydroxy phenyl)-1H-pyrazoles-5-yl]-3-(naphthalene-1-yl) urea (0.40g, 20%).
1HNMR(DMSO-d
6)：δ9.0(s，1H)，8.8(s，1H)，8.1-6.8(m，11H)，6.4(s，1H)，1.3(s，9H)。MS(ESI)m/z：401(M+H
+)。
Embodiment 42
According to the mode that is similar to embodiment 41, use embodiment 40 (2.00g, 5mmol) synthesising title compound, produce crystallisate, filter and wash, produce the 1-[3-tertiary butyl-1-(3-hydroxy phenyl)-IH-pyrazoles-5-yl with MeOH]-3-(4-chloro-phenyl-) urea (1.14g, 60%).HPLC purity: 96%; Mp:214-216;
1H NMR (CDC
13): δ 8.4 (s, 1H), 7.7 (s, 1H), 7.4-6.6 (m, 9H), 1.3 (s, 9H).
EXAMPLE V
Raw material, 1-[4-(amino methyl) phenyl]-the 3-tertiary butyl-N-nitroso-group-1H-pyrazoles-5-amine, according to the mode that is similar to embodiment A, use 4-aminobenzamide and 4,4-dimethyl-3-oxygen valeronitrile is synthetic.
1L four neck round-bottomed flasks are furnished with stirring rod, do Ar source, heating mantles and reflux exchanger.Use the argon cleaning flask, the raw material (12g, the 46.5mmol that pack into and react previously; 258.1g/mol) and anhydrous THF (500ml).This solution LiAlH
4(stirring reaction spends the night for 2.65g, 69.8mmol) handled.Reacting by heating refluxes, and all adds other LiAlH
4(the adding total amount is 8.35g).The cooling reaction adds H in order to 0 ℃
20(8.4ml), 15%NaOH (8.4ml) and H
20(24ml); Stirred this mixture 2 hours, and by the diatomite filtration solid, thoroughly washed with THF, vacuum concentrated solution produces 1-(4-(amino methyl-3-methoxyl group) the phenyl)-3-tertiary butyl-1H-pyrazoles-5-amine (6.8g), is oily matter.
A 40mL bottle is furnished with stirring rod, partition and Ar source.In bottle, pack into the raw material that reacts previously (2g, 8.2mmol, 244.17g/mol) and CHCL
3(15mL), under Ar, be cooled to 0 ℃, in 2 minutes, drip and be dissolved in CHCL
3Dimethyl dicarbonate butyl ester (5mL) (1.9g, 9.0mmol).Mixture is handled with 1N KOH (2mL), adds in 2 hours.Add saturated NaC
1The broken emulsion that produces of solution, separating layer, water CH
2C
12(2 * 1.5ml) extractions.The organic phase Na that merges
2SO
4Drying is filtered, vacuum concentration, and [4-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl)-2-methoxy-benzyl t-butyl carbamate (2.23g, 79%) is faint yellow solid in generation.
1HNMR(CDCl
3)：δ7.4(m，5H)，5.6(s，1H)，4.4(d，2H)，1.5(s，9H)，1.3(s，9H)。
Embodiment 43
A 40mL bottle is furnished with partition, stirring rod and Ar source, and (2g 5.81mmol), with the Ar flushing, and is dissolved in CHCL to the EXAMPLE V of packing into
3(20mL).(984mg is 5.81mmol) at CHCL with 2-naphthyl isocyanic ester for solution
3Handle (5mL), add in 1 minute.Stirring reaction 8 hours adds 1-naphthyl isocyanic ester (81mg) again, and stirring reaction spends the night.Cross filter solid, use CH
2C
12Washing produces the 4-[3-tertiary butyl-5-(3-naphthalene-1-yl) urea groups]-the 1H-pyrazol-1-yl] benzylamino t-butyl formate (1.2g).HPLC purity: 94.4%;
1H NMR (DMSO-d
6): δ 9.1 (s, 1H), 8.8 (s, 1H), 8.0 (m, 3H), 7.6 (m, 9H), 6.4 (s, 1H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
Embodiment 44
According to the mode that is similar to embodiment 43, use EXAMPLE V (2.0g, 5.81mmol) and right-chloro-phenyl-isocyanic ester (892mg) synthesising title compound, produce the 4-[3-tertiary butyl-5-(3-(4-chloro-phenyl-) urea groups)-1H-pyrazol-1-yl] benzylamino t-butyl formate (1.5g).HPLC purity: 97%;
1H NMR (DMSO-d
6): δ 9.2 (s, 1H), 8.4 (s, 1H), 7.4 (m, 8H), 6.4 (s, 1H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).
Embodiment 45
With 10mL flask of being furnished with stirring rod of Ar flushing, and the embodiment 43 that packs into (770mg, 1.5mmol) and CH
2C
12(1ml) with 1: 1CH
2C
12: TFA (2.5mL).1.5 after hour, vacuum concentration reaction mixture, resistates are dissolved among the EtOAc (15mL), use saturated NaHCO
3(10mL) with saturated NaC
1(10mL) washing.Dry organic layer filters and vacuum concentration, produces the 1-{3-tertiary butyl-1-[4-(amino methyl) phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea (710mg).
1H NMR(DMSO-d
6)：δ7.4(m，11H)，6.4(s，1H)，3.7(s，2H)，1.3(s，9H)。
Embodiment 46
According to the mode that is similar to embodiment 45, use embodiment 44 (1.5g, 1.5mmol) synthesising title compound produce the 1-3-tertiary butyl-1-[4-(amino methyl) phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea (1.0g).HPLC purity: 93.6%; Mp:100-102;
1H NMR (CDCl
3): δ 8.6 (s, 1H), 7.3 (m, 8H), 6.3 (s, 1H), 3.7 (brs, 2H), 1.3 (s, 9H).
Embodiment 47A
Under Ar, (260mg is 63mmol) with anhydrous EtOH (3mL) for the embodiment 45 that packs in a 10ml bottle.(0.63mmol), stirring at room was reacted 1.5 hours for 63 μ L, 74mg to drip divinyl sulfone in 3 minutes.Vacuum concentration produces yellow solid, and this solid is by preparation TLC purifying, at 5%MeOH:CH
2C
12The middle expansion.Cut main bands of a spectrum, with 1: 1EtOAc: the MeOH eluting silica gel, filter, vacuum concentration produces the 1-{3-tertiary butyl-1-[4-(1,1-sulphur dioxide morpholine-4-yl) aminomethyl phenyl]-1H-pyrazoles-5-yl }-3-(naphthalene-1-yl) urea (150mg).HPLC purity: 96%;
1H NMR (DMSO-d
6): δ 9.1 (s, 1H), 9.0 (s, 1H), 7.9 (m, 3H), 7.5 (m, 8H), 6.4 (s, 1H), 3.1 (brs, 4H), 2.9 (brs, 4H), 1.3 (s, 9H).
Embodiment 48
According to the mode that is similar to embodiment 47, use embodiment 46 (260mg, 0.66mmol) synthesising title compound, produce the 1-{3-tertiary butyl-1-[4-(1,1-sulphur dioxide morpholine-4-yl) aminomethyl phenyl]-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea (180mg).HPLC purity: 93%; Mp:136-138;
1H NMR (DMSO-d
6): δ 9.2 (s, 1H), 8.5 (s, 1H), 7.4 (m, 9H), 6.4 (s, 1H), 3.1 (brs, 4H), 3.0 (brs, 4H), 1.3 (s, 9H).
Embodiment 49
0 ℃, at chloro sulfonyl isocyanate (0.35g, CH 5mmol)
2C
12(0.18g, 5mmol), adding speed should make temperature of reaction be no more than 5 ℃ (20mL) to add tetramethyleneimine in the solution.Stir after 2 hours, add embodiment 41 (1.10g, 6.5mmol) and triethylamine (0.46g, CH 9mmol)
2C
12(20mL) solution.Finish when adding, heated mixt to room temperature and stirring spent the night.Reaction mixture is poured into by NaC
1Saturated 10%HCL (10mL) separates organic layer, and water layer extracts with ether.Organic layer drying (the Na that merges
2SO
4) and vacuum concentration, by preparation HPLC purifying, produce (tetramethyleneimine-1-carbonyl) the thionamic acid 3-[3-tertiary butyl-5-(3-naphthalene-1-base-urea groups)-pyrazol-1-yl] phenyl ester (40mg).
1H NMR(CDCl
3)：δ9.12(brs，1H)，8.61(brs，1H)，7.85-7.80(m，3H)，7.65(d，J＝8.0Hz，2H)，7.53-7.51(m，1H)，7.45-7.25(m，5H)，6.89(s，4H)，3.36-3.34(brs，1H)，3.14-3.13(brs，2H)，1.69(brs，2H)，1.62(brs，2H)，1.39(s，9H)；MS(ESI)m/z：577(1M+H
+)。
Embodiment 50
According to the mode that is similar to embodiment 49, use embodiment 42 synthesising title compounds, produce (tetramethyleneimine-1-carbonyl) the thionamic acid 3-[3-tertiary butyl-5-(4-chloro-phenyl--1-base-urea groups) pyrazol-1-yl] phenyl ester.MS(ESI)m/z：561(M+H
+)。
Embodiment W
Solid hydrochloric acid 4-p-methoxy-phenyl hydrazine (25.3g) is suspended in the toluene (100mL), handles with triethylamine (20.2g).This mixture of stirring at room 30 minutes is with pivalyl acetonitrile (18g).Reacting by heating is to refluxing and stirring and spend the night.Filtering heat mixture, the solid hexane wash, vacuum-drying obtains the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-amine (25g, 70%).
1H NMR(DMSO-d
6)：δ7.5(d，2H)，7.0(d，1H)，6.4(s，1H)，6.1(s，2H)，3.9(s，3H)，1.3(s，9H)。
Embodiment 51
Anhydrous CH at 1-isocyanic acid-4-methoxyl group-naphthalene (996mg)
2C
12(20mL) add embodiment W (1.23g) in the solution.Stirring reaction solution 3 hours filters the white depositions that produces, and handles with 10%HCL, from the MeOH recrystallization, vacuum-drying produces the 1-[3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-3-(1-methoxynaphthalene-4-base-urea, be white crystals (900mg, 40%).HPLC purity: 96%; Mp:143-144;
1HNMR (DMSO-d
6): δ 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.6 (m, 5H), 7.1 (d, 2H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H); 1.3 (s, 9H).
Embodiment 52
According to the mode that is similar to embodiment 51, use embodiment W and right-bromophenyl isocyanic ester (990mg) synthesising title compound, produce the 1-{3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl }-3-(4-bromophenyl) urea, be canescence crystallization (1.5g, 68%).HPLC purity: 98%; Mp:200-201;
1H NMR (DMSO-d
6): δ 9.3 (s, 1H), 8.3 (s, 1H), 7.4 (m, 6H), 7.0 (d, 2H), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).
Embodiment 53
According to the mode that is similar to embodiment 51, use embodiment W and right-chloro-phenyl-isocyanic ester (768mg) synthesising title compound, produce the 1-{3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea, be white crystals (1.3g, 65%).HPLC purity: 98%; Mp:209-210;
1HNMR (DMSO-d
6): δ 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (m, 4H), 7.3 (d, 2H), 7.1 (d, 2H), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).
Embodiment 54
According to the mode that is similar to embodiment 41, use embodiment 53 (500mg) synthesising title compound, produce the 1-{3-tertiary butyl-1-(4-hydroxy phenyl)-1H-pyrazoles-5-yl }-3-(4-chloro-phenyl-) urea, be white crystals (300mg, 62%).HPLC purity: 94%; Mp:144-145;
1H NMR (DMSO-d
6): δ 9.7 (s, 1H), 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (d, 2H), 7.3 (m, 4H); 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H).
Embodiment 55
According to the mode that is similar to embodiment 41, use embodiment 52 (550mg) synthesising title compound, produce 1-(the 3-tertiary butyl-1-(4-hydroxy phenyl)-1H-pyrazoles-5-yl)-3-(4-bromophenyl) urea, be white crystalline solid (400mg, 70%).HPLC purity: 93%; Mp:198 200;
1H NMR (DMSO-d6): δ 9.7 (s, 1H), 9.2 (s, 1H), 8.3 (s, 1H), 7.4 (d, 4H), 7.2 (m, 2H), 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H).
Embodiment X
Adopt Regan, etc., J.Med.Chem., 45,2994 (2002) methods prepare 4-(the 3-tertiary butyl-5-amino-1H-pyrazol-1-yl) methyl benzoate (3.67mmol) by 4-hydrazino-benzoic acid methyl esters and pivalyl acetonitrile.
Embodiment 56
A 500mL round-bottomed flask is furnished with magnetic stirring bar and ice bath.The embodiment X (1g) that packs in flask is dissolved in CH with it
2C
12(100mL).Add saturated sodium bicarbonate (100mL), stir the mixture rapidly, cool off in ice bath, handle with trichloromethylchloroformate (1.45g), mixture 1 hour stirs.Separating layer, CH
2C
12Layer is handled with the trimethyl carbinol (1.07g), and stirring at room solution spends the night.Solution H
20(2 * 150mL) washings, dry (Na
2SO
4), filter, vacuum concentration, by the flash chromatography purifying, use 1: 2 ethyl acetate: hexane produces 1-(4-(methoxycarbonyl) the phenyl)-3-tertiary butyl-1H-pyrazoles-5-aminocarbamic acid tert-butyl ester (100mg) as elutriant, is pale solid.
1HNMR(DMSO-d
6)：δ9.2(s，1H)，8.1(d，2H)，7.7(d，2H)，6.3(s，1H)，3.3(s，3H)，1.3(s，18H)。
Embodiment 57
According to the mode that is similar to embodiment 41, use embodiment X (1.37g) and right-chloro-phenyl-isocyanic ester (768mg) synthesising title compound, generation 4-(the 3-tertiary butyl-5-[3-(4-chloro-phenyl-) urea groups]-the 1H-pyrazol-1-yl) methyl benzoate, be white crystals (1.4g 66%).HPLC purity: 98%; Mp:160-161;
1H NMR (DMSO-d
6): δ 9.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (d, 2H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H).
Embodiment 58
According to the mode that is similar to embodiment 41, use embodiment K (1.27g) and 1-isocyanic acid-4-methoxyl group-naphthalene (996mg) synthesising title compound, produce the 4-{3-tertiary butyl-5-[3-(1-methoxynaphthalene-4-yl) urea groups]-the 1H-pyrazol-1-yl } methyl benzoate, be white crystals (845mg, 36%).HPLC purity: 98%; Mp:278-280;
1H NMR (DMSO-d
6): δ 8.76 (s, 1H), 8.73 (s, H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (d, 2H), 7.6 (m, 3H), 7.0 (d, 1H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 1.3 (s, 9H).
Embodiment 59
According to the mode that is similar to embodiment 41, use embodiment X (1.37g) and right-bromophenyl isocyanic ester (990mg) synthesising title compound, produce the 4-{3-tertiary butyl-5-[3-(4-bromophenyl) urea groups]-the 1H-pyrazol-1-yl } methyl benzoate, be white crystals (1.4g, 59%).HPLC purity: 94%; Mp:270272;
1H NMR (DMSO-d
6): δ 9.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 7.4 (d, 4H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H).
Embodiment 60
At-78 ℃, in 10 minutes, in the 30mL toluene solution of embodiment 59 (700mg), drip hydrogenation diisobutyl ammonium toluene (1M in toluene, 7.5mL) solution.-78 ℃ of stirred reaction mixtures 30 minutes stirred 30 minutes at 0 ℃ then.The vacuum concentration reaction mixture is used H to dry
20 handles.Cross filter solid, and use acetonitrile treatment.Evaporating solns is to doing, and resistates is dissolved in ethyl acetate, adds hexane and precipitates, and obtains yellow solid, and is dry under the vacuum, obtains the 1-[3-tertiary butyl-1-(4-methylol) phenyl]-1H-pyrazoles-5-yl] urea (400mg, 61%).HPLC purity: 95%;
1H NMR (DMSO-d
6): δ 9.2 (s, 1H), 8.4 (s, 1H), 7.5 (m, 8H), 6.4 (s, 1H), 5.3 (t, 1H), 4.6 (d, 2H), 1.3 (s, 9H).
Embodiment 1 embodiment 2
Embodiment 3 embodiment 4
Embodiment 5 embodiment 6
Wherein, Y is O, S, NR
6,-NR
6SO
2-, NR
6CO-, alkylidene group, O-(CH
2) n-, NR
6-(CH
2) n-, one of them MU (methylene unit) is replaced by oxo group, or Y is a direct key; D takes from the group that Fig. 1 identifies:
Fig. 1
Embodiment 7 embodiment 8
Embodiment 9 embodiment 10
Embodiment 11 embodiment 12
Embodiment 13 embodiment 14
Embodiment 15 embodiment 16
Embodiment 17 embodiment 18
Embodiment 19 embodiment 20
Embodiment 21 embodiment 22
Embodiment 23 embodiment 24
Embodiment 25 embodiment 26
Embodiment 27 embodiment 28
Embodiment 29 embodiment 30
Embodiment 31 embodiment 32
Embodiment 33 embodiment 34
Embodiment 35 embodiment 36
Embodiment 37 embodiment 38
Embodiment 39 embodiment 40
Embodiment 41 embodiment 42
Embodiment 43 embodiment 44
Embodiment 45 embodiment 46
Embodiment 47 embodiment 48
Embodiment 49 embodiment 50
Embodiment 51 embodiment 52
Embodiment 53 embodiment 54
Embodiment 55 embodiment 56
Embodiment 57 embodiment 58
Embodiment 59 embodiment 60
Embodiment 61 embodiment 62
Embodiment 63 embodiment 64
Embodiment 65 embodiment 66
Embodiment 67 embodiment 68
Embodiment 69 embodiment 70
Embodiment 71 embodiment 72
Embodiment 73 embodiment 74
Embodiment 75 embodiment 76
Embodiment 77 embodiment 78
Wherein, X or Y are O, S, NR
6,-NR
6SO
2-, alkylidene group, O-(CH
2)
n-, NR
6-(CH
2)
n, one of them methylene radical is replaced by the oxo base, or X or Y are direct keys; D takes from the group of identifying among Fig. 1:
Fig. 1
Object lesson of the present invention is illustrated by following structural formula:
Embodiment 79 embodiment 80
Embodiment 81 embodiment 82
Embodiment 83 embodiment 84
Embodiment 85 embodiment 86
Embodiment 87 embodiment 88
Embodiment 89 embodiment 90
Embodiment 91 embodiment 92
Embodiment 93 embodiment 94
Embodiment 95 embodiment 96
Embodiment 97 embodiment 98
Embodiment 99 embodiment 100
Embodiment 101 embodiment 102
Embodiment 103 embodiment 104
Embodiment 105 embodiment 106
Embodiment 107 embodiment 108
Embodiment 109 embodiment 110
Embodiment 111 embodiment 112
Embodiment 113 embodiment 114
Embodiment 115 embodiment 116
Embodiment 117 embodiment 118
Embodiment 119 embodiment 120
Embodiment 121 embodiment 122
Embodiment 123 embodiment 124
Embodiment 125 embodiment 126
Embodiment 127 embodiment 128
Embodiment 129 embodiment 130
Embodiment 131 embodiment 132
Embodiment 133 embodiment 134
Embodiment 135 embodiment 136
Embodiment 137 embodiment 138
Embodiment 139 embodiment 140
Embodiment 141 embodiment 142
Embodiment 143 embodiment 144
Above-mentioned all reference are all included this paper in as a reference.In addition, also include the application of two whiles in, promptly in the " adjusting of protein function degree " the Modulaion of Protein Functionalities " S/N______ of in December, 2003 _ day submission, and " cancer therapy drug " " Anti-InflammatoryMedicaments " that submits in December, 2003 _ day, S/N________.
Sequence table
＜110〉Deciphera Pharmaceuticals LLC (Deciphera Pharmaceuticals, Inc.)
D. Fehling (Flynn, Daniel)
P. Lip river in the Peter (Petillo, Peter)
＜120〉anti-inflammatory drug
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<150>US 60/437,415
<151>2002-12-31
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Ile Trp Glu Val Pro Glu Arg Tyr Gln Asn Leu Ser Pro Val Gly Ser
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Gly Ala Tyr Gly Ser Val Cys Ala Ala Phe Asp Thr Lys Thr Gly Leu
35 40 45
Arg Val Ala Val Lys Lys Leu Ser Arg Pro Phe Gln Ser Ile Ile His
50 55 60
Ala Lys Arg Thr Tyr Arg Glu Leu Arg Leu Leu Lys His Met Lys His
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Glu Asn Val Ile Gly Leu Leu Asp Val Phe Thr Pro Ala Arg Ser Leu
85 90 95
Glu Glu Phe Asn Asp Val Tyr Leu Val Thr His Leu Met Gly Ala Asp
100 105 110
Leu Asn Asn Ile Val Lys Cys Gln Lys Leu Thr Asp Asp His Val Gln
115 120 125
Phe Leu Ile Tyr Gln Ile Leu Arg Gly Leu Lys Tyr Ile His Ser Ala
130 135 140
Asp Ile Ile His Arg Asp Leu Lys Pro Ser Asn Leu Ala Val Asn Glu
145 150 155 160
Asp Cys Glu Leu Lys Ile Leu Asp Phe Gly Leu Ala Arg His Thr Asp
165 170 175
Asp Glu Met Thr Gly Tyr Val Ala Thr Arg Trp Tyr Arg Ala Pro Glu
180 185 190
Ile Met Leu Asn Trp Met His Tyr Asn Gln Thr Val Asp Ile Trp Ser
195 200 205
Val Gly Cys Ile Met Ala Glu Leu Leu Thr Gly Arg Thr Leu Phe Pro
210 215 220
Gly Thr Asp His Ile Asp Gln Leu Lys Leu Ile Leu Arg Leu Val Gly
225 230 235 240
Thr Pro Gly Ala Glu Leu Leu Lys Lys Ile Ser Ser Glu Ser Ala Arg
245 250 255
Asn Tyr Ile Gln Ser Leu Thr Gln Met Pro Lys Met Asn Phe Ala Asn
260 265 270
Val Phe Ile Gly Ala Asn Pro Leu Ala Val Asp Leu Leu Glu Lys Met
275 280 285
Leu Val Leu Asp Ser Asp Lys Arg Ile Thr Ala Ala Gln Ala Leu Ala
290 295 300
His Ala Tyr Phe Ala Gln Tyr His Asp Pro Asp Asp Glu Pro Val Ala
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Asp Pro Tyr Asp Gln Ser Phe Glu Ser Arg Asp Leu Leu Ile Asp Glu
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Trp Lys Ser Leu Thr Tyr Asp Glu Val Ile Ser Phe Val Pro Pro Pro
340 345 350
Leu Asp Gln Glu Glu Met Glu Ser
355 360
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1
Claims (31)
1. compound with following formula:
In the formula: R
1Be selected from aryl and heteroaryl;
X and Y are selected from independently of one another :-O-,-S-,-NR
6-,-NR
6SO
2-,-NR
6CO-, alkynyl, thiazolinyl, alkylidene group ,-O (CH
2)
h-and-NR
6(CH
2) h-, wherein h is selected from independently of one another: 1,2,3 or 4 and to alkylidene group, and-O (CH
2)
h-and-NR
6(CH
2)
h-in each, wherein in the methylene radical of Cun Zaiing one can choose two keys wantonly and be connected to side chain oxygen base, except-O (CH
2)
h-introduce side chain oxygen base not form ester moiety;
A is selected from: aromatics, monocyclic heterocycles and bicyclic heterocycles;
D is phenyl or five-unit or six-first heterocycle, is selected from pyrazolyl, pyrryl, imidazolyl ， oxazolyl, thiazolyl, furyl, pyridyl and pyrimidyl;
E is selected from: phenyl, pyridyl * and pyrimidyl *;
L is selected from :-C (O)-and-S (O)
2-;
J is 0 or 1;
M is 0 or 1;
N is 0 or 1;
P is 0 or 1;
Q is 0 or 1;
T is 0 or 1;
Q is selected from following:
R
4Group is selected from independently of one another :-H, and alkyl, aminoalkyl group, alkoxyalkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl are except when R
4Substituting group is placed with a heteroatoms on the α carbon that is directly connected to ring nitrogen on the Q;
As two R
4When being connected with homoatomic, two R
4Optional alicyclic ring or the heterocycle that forms 4-7 unit of group;
R
5Be selected from independently of one another :-H, alkyl, aryl, heterocyclic radical, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy, alkylthio, arylthio, cyano group, halogen, perfluoroalkyl, alkyl-carbonyl and nitro;
R
6Be selected from independently of one another :-H, alkyl, allyl group and β-trimethyl silyl ethyl;
R
8Be selected from independently of one another: alkyl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R
9Group is selected from independently of one another :-H, and-F and alkyl, wherein, as two R
9When group was the alkyl of geminal, the alkyl of described geminal can cyclisation form 3-6 unit ring;
Z is selected from independently of one another :-O-and-N (R
4)-;
Each ring is chosen wantonly and is comprised one or more R in the formula (I)
7, R wherein
7Be non-interfering substituent, be independently selected from :-H, alkyl, aryl, heterocyclic radical, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy, alkylthio, arylthio, cyano group, halogen, nitrilo, nitro, the alkyl sulfinyl, alkyl sulphonyl, amino-sulfonyl and perfluoroalkyl;
Except: when Q was Q-3 or Q-4, then formula (I) compound was not following compound:
When Q is Q-7, q is 0, R
5When being phenyl with D, then A is not a phenyl ， oxazolyl, pyridyl, pyrimidyl, pyrazolyl or imidazolyl;
When Q is Q-7, R
5Be-OH, Y is-O-,-S-or-CO-, m is 0, n is 0, p be 0 and A be phenyl, pyridyl or thiazolyl, then D is not a thienyl, thiazolyl or phenyl;
When Q is Q-7, R
5Be-OH, m is 0, and n is 0, and p is 0, t be 0 and A be phenyl, when pyridyl or thiazolyl, then D is not a thienyl, thiazolyl or phenyl;
When Q was Q-7, then formula (I) compound was not following compound
R
80Be H, Me R
81It is the phenyl that replaces
R
82It is the phenyl that replaces
When Q was Q-8, then Y was not-CH
2O-;
When Q was Q-8, formula (I) compound was not following compound
R
10=alkyl, aryl, alkoxy aryl alkyl or aralkyl
When Q was Q-9, then formula (I) compound was not following compound:
R
11=H, alkyl, alkoxyl group, nitro, halogen R
12R
13=H, alkyl R
14=H, alkyl, allyl group, propargyl
R
15=H, alkyl
R
16=H, methyl R
17, R
18=alkyl R
19=H, alkyl
When Q is Q-10, t is 0 and E when being phenyl, and then E goes up any R
7It or not the o-alkoxyl group;
When Q was Q-10, then formula (I) compound was not following compound
When Q is Q-11, t is 0 and E when being phenyl, and then E goes up any R
7It or not the o-alkoxyl group;
When Q was Q-11, then formula (I) compound was not following compound
When Q was Q-15, then formula (I) compound was not following compound
R
20The phenyl of=replacement, R
21=H, alkyl
When Q is Q-16, Y is-during NH-,
The following formula of formula (I) is not an xenyl;
When Q is Q-16, Y is-during S-,
Then the following formula of formula (I) is not phenyl sulfonyl amino phenyl or phenylcarbonyl group aminophenyl;
When Q is Q-16, Y is-SO
2During NH-, then formula (I) compound is not following compound:
R
23＝OH，SH，NH
2
R
24=H or one or more methoxyl group, hydroxyl, fluorine, chlorine,
Nitro, dimethylamino, or furyl
R
25Phenyl, the furyl of=replacement
R
26=OH or C
1
X
5＝O，NH
When Q is Q-16, Y is-during CONH-, then the following formula of formula (I) is not the imidazo phenyl;
When Q is Q-16, Y is-during CONH-, then formula (I) compound is not following compound
R
27The phenyl of=replacement, the pyridyl carbonyl
R
28=CN, methoxycarbonyl
N=0 or 1
When Q is Q-16, t is 0 o'clock, and then the following formula of formula (I) is not the phenylcarbonyl group phenyl, Mi Dingbing phenyl, phenyl pyrimidine base, pyrimidyl or N-pyrryl;
When Q was Q-17, then formula (I) compound was not following compound
Or
R
29=alkyl R
31The phenyl of=replacement
R
30=H, the tertiary butyl, benzoyl
When Q was Q-21, then formula (I) compound was not following compound
When Q is Q-22, below then formula (I) compound is selected from:
When Q is Q-22, q is 0 o'clock, below then formula (I) compound is selected from:
But do not comprise following compound
Between or to R
34=Me, C
1Between or to R
37=N (Me)
2, morpholinyl, OMe, OH, H
R
35=N (Me)
2, morpholine R
38=H, CN, OMe, OH, benzyloxy, phenyl,
For nitro
R
36＝H，F R
39＝H，OH
R
40＝H，F
R
41＝H，C
1
Between or to or right
Between or right
When Q was Q-23, then formula (I) compound was not following compound
When Q is Q-24, Q-25, when Q-26 or Q-31, below then formula (I) compound is selected from:
Wherein, W is selected from independently of one another :-CH-and-N-;
G
1Be selected from independently of one another :-O-,-S-and-N (R
4)-;
* mark the following Q-24 of being connected to, Q-25, the site of Q-26 or Q-31:
Wherein, Z is selected from independently of one another :-O-and-N (R
4)-;
When Q was Q-31, then formula (I) compound was not following compound:
Or
When Q is Q-28 or Q-29, t is 0 o'clock, and then formula (I) compound is not following compound:
R
46=H, hydroxyalkyl, alkoxyl group alkoxyl group, hydroxyl
When Q is Q-28 or Q-29, when Y was ehter bond, then formula (I) compound was not following compound:
Or
When Q is Q-28 or Q-29, Y is-during CONH-, then formula (I) compound is not following compound:
When Q was Q-32, then following formula was not an xenyl, benzoxazolyl phenyl, pyridyl phenyl or bipyridyl;
When Q is Q-32, Y is-CONH-, and q is 0, and m is 0, and the following formula of formula (I) is-and during CONH-, then A is not a phenyl;
When Q was Q-32, q was 0, and m is 0, following formula is-and during CONH-,
Then formula (I) compound is not following compound:
R
47=alkyl, the phenyl of replacement, thienyl, phenylacetyl, R
54=benzoyl, Phenylalkylamino carbonyl, replacement
Naphthyl phenyl amino carbonyl, H, Br
R
48=H, alkyl, Br, the phenyl of replacement, benzoyl, R
55=C
1, Br, SPh, benzoyl, phenyl sulfonyl
Phenyl sulfonyl R
51=H, phenyl sulfonyl, phenyl, benzyl
R
49=H, alkyl, phenyl R
6=Et, i-Pr
R
50The phenyl R of=replacement
53The phenyl of=replacement, the benzyl of replacement
X
1=O, N-Ph, N-alkyl, N-formamyl
Z
1＝N(R
50)，O
When Q is Q-32, D is a thiazolyl, and q is 0, and t is 0, and p is 0, n be 0 and m be 0 o'clock, then A is not phenyl or 2-pyridone;
When Q is Q-32, D Shi oxazolyl Huo isoxazolyl, q is 0, t is 0, p is 0, n be 0 and m be 0 o'clock, then A is not a phenyl;
When Q is Q-32, D is that pyrimidyl q is 0, and t is 0, and p is 0, n be 0 and m be 0 o'clock, then A is not a phenyl;
When Q is Q-32, when Y was ehter bond, then the following formula of formula (I) was not xenyl or Ben Ji oxazolyl;
When Q is Q-32, Y is-during CH=CH-, then the following formula of formula (I) is not the phenyl amino phenyl;
When Q was Q-32, then formula (I) compound was not following compound:
b＝0-1
x
1＝O，S
R
56=H, CF
3, C
1, imidazolyl, amino, morpholino, thiophenyl,
Cycloalkyl, benzyl, phenyl, phenoxy group, thienyl, the alkane of replacement
Base, pyridyl sulphur, pyrimidyl, benzylamino, the N-benzimidazolyl-,
The pyridine carbonylamino, urea groups, N-thioureido, the silane alcohol base ammonia of replacement
Base, phenyl sulfonyl, substituted benzoyl, octadecyloxy phenyl alcohol radical, furan
The base of muttering, the thiophene acyl group, pyridine acyl,
R
57The phenyl of=replacement, the xenyl of replacement
Or
With
R
58The alkyl amino-carbonyl of=replacement, phenyl amino carbonyl d=0.2
R
59=H, C
1R
50=H, alkyl
R
61The phenyl of=replacement, thienyl, Br
R
62=H, alkyl, phenyl
R
63The phenyl of=replacement
When Q is Q-35, as follows:
Wherein G is selected from :-O-,-S-,-NR
4-and-CH
2-, k be 0 or 1 and u be 1,2,3 or 4, following formula then
Be selected from following:
Except formula (I) compound is not following:
R
71=H, Me R
72=thiazolyl ， isoxazolyl, imidazoles 28.1 R
73=OCH
2CO
2Between H, right
W
4=N, CH base, furyl R
74The=oxazolyl, imidazolyl R
75=H, Et
28.2 R
73＝CO
2Me R
76＝H，NH
2，NO
2
R
74=chloro-phenyl-n=0-1
2. compound as claimed in claim 1 is characterized in that R
1Be selected from: 6-5 condensed heteroaryl, 6-5 annelated heterocycles base, 5-6 condensed heteroaryl and 5-6 annelated heterocycles base.
3. compound as claimed in claim 2 is characterized in that R
1Be selected from following:
R
2Be selected from independently of one another :-H, alkyl, amino, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, halogen, alkoxyl group and hydroxyl;
R
3Be selected from independently of one another :-H, alkyl, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, alkoxyl group, hydroxyl, cyano group, halogen, perfluoroalkyl, alkyl sulfinyl, alkyl sulphonyl, R
4NHSO
2-and-NHSO
2R
4With
V is selected from: O and H
2
4. compound as claimed in claim 1 is characterized in that A is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrryl, thiazolyl ， oxazolyl, imidazolyl, indyl, indazolyl, benzimidazolyl-, benzotriazole base, isoquinolyl, quinolyl, benzothiazolyl, benzofuryl, benzothienyl, pyrazolyl pyrimidyl, imidazopyrimidine base, purine radicals and following formula
W wherein
1Be selected from independently of one another :-CH-and-N-.
5. method of regulating p38 Dihydrostreptomycin-6-phosphate 3'alpha-kinase activated state comprises following step: described kinases is contacted with the compound with following formula:
In the formula: R
1Be selected from aryl and heteroaryl;
X and Y are selected from independently of one another :-O-,-S-,-NR
6-,-NR
6SO
2-,-NR
6CO-, alkynyl, thiazolinyl, alkylidene group ,-O (CH
2)
h-and-NR
6(CH
2)
h-, wherein h is selected from independently of one another: 1,2,3 or 4 and to alkylidene group, and-O (CH
2)
h-and-NR
6(CH
2)
h-in each, wherein in the methylene radical of Cun Zaiing one can choose two keys wantonly and be connected to side chain oxygen base, except-O (CH
2)
h-introduce side chain oxygen base not form ester moiety;
A is selected from: aromatics, monocyclic heterocycles and bicyclic heterocycles;
D is phenyl or five-unit or six-first heterocycle, is selected from pyrazolyl, pyrryl, imidazolyl ， oxazolyl, thiazolyl, furyl, pyridyl and pyrimidyl;
E is selected from: phenyl, pyridyl * and pyrimidyl *;
L is selected from :-C (O)-and-S (O)
2-;
J is 0 or 1;
M is 0 or 1;
N is 0 or 1;
P is 0 or 1;
Q is 0 or 1;
T is 0 or 1;
Q is selected from following:
R
4Group is selected from independently of one another :-H, and alkyl, aminoalkyl group, alkoxyalkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl are except when R
4Substituting group is placed with a heteroatoms on the α carbon that is directly connected to ring nitrogen on the Q, as two R
4When group is connected with same atom, two R
4Optional alicyclic ring or the heterocycle that forms 4-7 unit of group;
R
5Be selected from independently of one another :-H, alkyl, aryl, heterocyclic radical, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy, alkylthio, arylthio, cyano group, halogen, perfluoroalkyl, alkyl-carbonyl and nitro;
R
6Be selected from independently of one another :-H, alkyl, allyl group and β-trimethyl silyl ethyl;
R
8Be selected from independently of one another: alkyl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R
9Be selected from independently of one another :-H ,-F and alkyl, wherein two R
9Group is the alkyl of geminal, and the alkyl of described geminal can cyclisation form 3-6 unit ring;
Z is selected from independently of one another :-O-and-N (R
4)-; Each ring of formula (II) is chosen wantonly and is comprised one or more R
7, R wherein
7Be non-interfering substituent, be independently selected from :-H, alkyl, aryl; heterocyclic radical, alkylamino, arylamino, cycloalkyl amino; heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy; alkylthio, arylthio, cyano group, halogen; nitrilo, nitro, alkyl sulfinyl; alkyl sulphonyl, amino-sulfonyl and perfluoroalkyl
Thereby regulate described activated state.
6. method as claimed in claim 5 is characterized in that described contact procedure is present in the zone of described kinase whose on-off control pocket.
7. method as claimed in claim 6 is characterized in that, described kinase whose on-off control pocket comprises the amino acid residue sequence that operationally is attached on described general formula (II) molecule.
8. method as claimed in claim 6 is characterized in that, described on-off control pocket is selected from on-off control pocket single, compound and combination.
9. method as claimed in claim 8 is characterized in that, described zone is selected from α-C spiral, α-D spiral, catalysis ring, described on-off control ligand sequence and described C-leaf residue and their combination.
10. method as claimed in claim 9 is characterized in that, described α-C spiral comprises SEQ ID NO.2.
11. method as claimed in claim 9 is characterized in that, described catalysis ring comprises SEQ ID NO.3.
12. method as claimed in claim 9 is characterized in that, described on-off control ligand sequence is selected from SEQ IDNO.4, SEQ ID NO.5 and their combination.
13. method as claimed in claim 9 is characterized in that, described C-leaf residue comprises SEQ ID NO.6.
14. method as claimed in claim 5 is characterized in that, described kinases is selected from total wild-type sequence and disease polymorph.
15. method as claimed in claim 5 is characterized in that, the state that described active state is selected from adjusted and regulates down.
16. method as claimed in claim 5 is characterized in that, described molecule is the antagonist of described kinase whose " opening " on-off control pocket.
17. method as claimed in claim 5 is characterized in that, described molecule is the agonist of described kinase whose " pass " on-off control pocket.
18. method as claimed in claim 5 is characterized in that, described method comprises that taking described molecule to individuality treats the step that is selected from following illness: people's inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, urarthritis, Sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, apoplexy, reperfusion injury, neural wound, neural ischemic, psoriatic, restenosis, chronic pulmonary inflammatory disease, the bone resorption disease, graft-vs-host reaction, ChronShi disease, ulcerative colitis, inflammatory bowel, pyrosis, and their combination.
19. method as claimed in claim 18 is characterized in that, described molecule is oral by being selected from, parenteral, suction and subcutaneous method are taken.
20. method as claimed in claim 5 is characterized in that, described molecule has the structure of the described compound of claim 1.
21. an affixture, it comprises and kinases bonded molecule, and described molecule has general formula
In the formula: R
1Be selected from: aryl and heteroaryl;
X and Y are selected from independently of one another :-O-,-S-,-NR
6-,-NR
6SO
2-,-NR
6CO-, alkynyl, alkenyl, alkylidene group ,-O (CH
2)
h-and-NR
6(CH
2)
h-, wherein h is selected from independently of one another: 1,2,3 or 4 and to alkylidene group, and-O (CH
2)
h-and-NR
6(CH
2)
h-in each, wherein in the methylene radical of Cun Zaiing one can choose two keys wantonly and be connected to side chain oxygen base, except-O (CH
2)
h-introduce side chain oxygen base not form ester moiety;
A is selected from: aromatics, monocyclic heterocycles and bicyclic heterocycles;
D is phenyl or five-unit or six-first heterocycle, is selected from pyrazolyl, pyrryl, imidazolyl ， oxazolyl, thiazolyl, furyl, pyridyl and pyrimidyl;
E is selected from: phenyl, pyridyl * and pyrimidyl *;
L is selected from :-C (O)-and-S (O)
2-;
J is 0 or 1;
M is 0 or 1;
N is 0 or 1;
P is 0 or 1;
Q is 0 or 1;
T is 0 or 1;
Q is selected from following:
R
4Be selected from independently of one another :-H, alkyl, aminoalkyl group, alkoxyalkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl are except when R
4Substituting group is placed with a heteroatoms on the α carbon that is directly connected to ring nitrogen on the Q;
As two R
4When being connected with homoatomic, two R
4Optional alicyclic ring or the heterocycle that forms 4-7 unit of group;
R
5Be selected from independently of one another :-H, alkyl, aryl, heterocyclic radical, alkylamino, arylamino, cycloalkyl amino, heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy, alkylthio, arylthio, cyano group, halogen, perfluoroalkyl, alkyl-carbonyl and nitro;
R
6Be selected from independently of one another :-H, alkyl, allyl group and β-trimethyl silyl ethyl;
R
8Be selected from independently of one another: alkyl, aralkyl, heterocyclic radical and heterocyclic radical alkyl;
R
9Group is selected from independently of one another :-H, and-F and alkyl, wherein, as two R
9When group was the alkyl of geminal, the alkyl of described geminal can cyclisation form 3-6 unit ring;
Z is selected from independently of one another :-O-and-N (R
4)-;
Each ring is chosen wantonly and is comprised one or more R in the formula (III)
7, R wherein
7Be non-interfering substituent, be independently selected from :-H, alkyl, aryl; heterocyclic radical, alkylamino, arylamino, cycloalkyl amino; heterocyclic radical amino, hydroxyl, alkoxyl group, aryloxy; alkylthio, arylthio, cyano group; halogen, nitrilo, nitro; alkyl sulfinyl, alkyl sulphonyl, amino-sulfonyl and perfluoroalkyl.
22. affixture as claimed in claim 21 is characterized in that, described molecule is combined in described kinase whose on-off control pocket area.
23. affixture as claimed in claim 22 is characterized in that, described kinase whose on-off control pocket comprises the amino acid residue sequence that operationally is attached on described general formula (III) molecule.
24. affixture as claimed in claim 22 is characterized in that, described on-off control pocket is selected from on-off control pocket single, compound and combination.
25. affixture as claimed in claim 24 is characterized in that, described zone is selected from α-C spiral, α-D spiral, catalysis ring, described on-off control ligand sequence and described C-terminal residue and their combination.
26. affixture as claimed in claim 25 is characterized in that, described α-C spiral comprises SEQ ID NO.2.
27. affixture as claimed in claim 25 is characterized in that, described catalysis ring comprises SEQ ID NO.3.
28. affixture as claimed in claim 25 is characterized in that, described on-off control ligand sequence is selected from SEQID NO.5, SEQ ID NO.6 and their combination.
29. affixture as claimed in claim 25 is characterized in that, described C-leaf residue comprises W197, M198, H199, Y200.
30. affixture as claimed in claim 21 is characterized in that, described kinases is selected from total wild-type sequence and disease polymorph.
31. affixture as claimed in claim 21 is characterized in that, described molecule has the structure of the described compound of claim 1.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
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| US43748702P | 2002-12-31 | 2002-12-31 | |
| US60/437,415 | 2002-12-31 | ||
| US60/437,304 | 2002-12-31 | ||
| US60/437,487 | 2002-12-31 | ||
| US60/437,403 | 2002-12-31 | ||
| US60/463,804 | 2003-04-18 | ||
| US10/746,460 | 2003-12-24 |
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ID=36689351
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| CN 200380110050 Pending CN1756747A (en) | 2002-12-31 | 2003-12-26 | Anti-inflammatory medicaments |
| CN 200380110049 Pending CN1756849A (en) | 2002-12-31 | 2003-12-26 | Modulation of protein functionalities |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796123A (en) * | 2011-05-25 | 2012-11-28 | 上海药明康德新药开发有限公司 | Piperidine sulfamide spiro-compound and preparation method thereof |
| CN102333770B (en) * | 2008-12-11 | 2015-01-28 | 瑞斯比维特有限公司 | P38 MAP kinase inhibitors |
| CN111358787A (en) * | 2020-03-26 | 2020-07-03 | 四川大学华西医院 | Application of heterocyclic compound in preparation of medicine for treating pneumonia |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2186810A1 (en) * | 2008-10-31 | 2010-05-19 | Institut Curie | Poly-heteroaryl derivatives for the treatment of cancer |
| CN110275010B (en) * | 2019-06-21 | 2022-07-01 | 中山大学孙逸仙纪念医院 | Screening method of P38a MAPK signal pathway inhibitor for prostate cancer treatment drug |
| CN110563624B (en) * | 2019-09-29 | 2021-08-24 | 河南科技大学 | 2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof |
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2003
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102333770B (en) * | 2008-12-11 | 2015-01-28 | 瑞斯比维特有限公司 | P38 MAP kinase inhibitors |
| CN102796123A (en) * | 2011-05-25 | 2012-11-28 | 上海药明康德新药开发有限公司 | Piperidine sulfamide spiro-compound and preparation method thereof |
| CN111358787A (en) * | 2020-03-26 | 2020-07-03 | 四川大学华西医院 | Application of heterocyclic compound in preparation of medicine for treating pneumonia |
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| Publication number | Publication date |
|---|---|
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| CN1791596A (en) | 2006-06-21 |
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